Pyrazole derivatives

ABSTRACT

The present invention relates to pyrazole derivatives of the formula (I), ##STR1## wherein R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , p and n are as defined on claim 1, or a salt thereof, and herbicides containing them as active ingredients.

This application is a continuation-in-part application of InternationalApplication PCT/JP94/01264 filed Aug. 1, 1994.

TECHNICAL FIELD

The present invention relates to novel pyrazole derivatives, herbicidescontaining the pyrazole derivatives as active ingredients, andintermediates suitable for the production of the pyrazole derivatives.

Technical Background and Problems which the Invention Seeks to Solve

Herbicides are very important chemicals for saving weed-controllinglabors and improving the yield of agricultural and horticultural cropsand have been therefore aggressively studied and developed for manyyears, and a diversity of herbicides have now been put to practical use.Today, however, it is still desired to develop novel chemicals havingexcellent herbicidal efficacy, particularly chemicals which canselectively control target weeds alone at a low dosage without causingphytotoxicity on crops.

During the time of planting corn, etc., a triazine-based herbicide suchas atrazine and acid anilide-based herbicides such as alachlor andmetolachlor have been conventionally used. However, atrazine shows lowefficacy to gramineous weeds, and on the other hand, alachlor andmetolachlor show low efficacy to broad-leaved weeds. It is thereforedifficult at present to control gramineous weeds and broad-leaved weedstogether simultaneously with a single herbicide. Further, the aboveherbicides are undesirable in view of an environmental problem due totheir high dosage requirement.

It is known that in paddy land, a variety of weeds, annual gramineousweeds such as barnyardgrass, annual cyperaceous weeds such as umbrellaplant, annual broad-leaved weeds such as monochoria and toothcup andperennial weeds such as sagitaria pygmaea, pondweed, oriental waterplantain, bulrush, needle spikerush, serotinus, water chestnut,arrowhead and dropwort grow together with paddy rice, and in ricecultivation, it is very important to effectively control these weeds ata low dosage in view of environmental pollution without causingphytotoxicity on paddy rice. Generally, it is known that chemicalshaving high herbicidal efficacy on barnyardgrass are liable to causephytotoxicity on paddy rice, and it is a particularly important subjectto develop a chemical which has high herbicidal efficacy onbarnyardgrass as a gramineous weed and has excellent inter-genusselectivity between paddy rice and barnyardgrass.

Meanwhile, it is known that specific 4-benzoylpyrazoles have herbicidalefficacy (JP-A-63-122672, JP-A-63-122673, JP-A-63-170365, JP-A-1-52759,JP-A-2-173 and JP-A-2-288866), and pyrazolate of the following chemicalformula is among herbicides commercially available at present. ##STR2##

Further, a compound (A), the typical example of 4-benzoylpyrazolederivatives disclosed in the above publications, has the followingchemical formula (Compound No. 35 in JP-A-2-173).

Compound (A): Compound No. 35 disclosed in JP-A-2-173 ##STR3##

The above 4-benzoylpyrazole derivatives have herbicidal activity, whiletheir herbicidal activity is practically insufficient. In particular,their herbicidal activity to gramineous weeds such as barnyardgrass andgreen foxtail is very poor. When they are used as a herbicide forcontrolling weeds in paddy land, they may cause phytotoxicity on paddyrice since they have poor selectivity between paddy rice and gramineousweeds.

The present inventors have therefore proposed pyrazole derivativeshaving a thiochroman ring and have filed patent applications directedthereto (JP-A-4-185526 and International Laid-open Patent PublicationWO93/18031). Typical examples (B) and (C) of the compounds disclosed inthe specifications of the above prior applications are as follows.

Compound (B): Compound No. 66 disclosed in International Laid-openPatent Publication WO93/18031 ##STR4##

Compound (C): Compound No. b-3 disclosed in JP-A-4-185526 ##STR5##

The above compounds have high herbicidal activity, while they still haveroom for improvement in view of safety to paddy rice.

The present invention has been made in view of the above circumstances,and the object thereof is to provide a pyrazole derivative which cancontrol a broad range of upland weeds and paddy land weeds, particularlybarnyardgrass in paddy land, at a low dosage without causingphytotoxicity on crops such as corn, paddy rice, etc., a herbicidecontaining the same, and an intermediate for obtaining the pyrazolederivative.

DISCLOSURE OF THE INVENTION

The first aspect of the present invention is directed to a pyrazolederivative of the general formula (I), ##STR6## wherein: R¹ is onemember selected from the group consisting of hydrogen, a C₁ ˜C₄ alkylgroup, a C₁ ˜C₄ haloalkyl group and a C₂ ˜C₄ alkoxyalkyl group;

R² is one member selected from the group consisting of a C₁ ˜C₄ alkylgroup, a C₂ ˜C₄ alkenyl group and a C₂ ˜C₄ haloalkenyl group;

X¹ is one member selected from hydrogen atom, halogen atom, a C₁ ˜C₄alkyl group, a C₁ ˜C₄ haloalkyl group, a C₂ ˜C₄ alkoxyalkyl group, a C₁˜C₄ alkoxy group and a C₁ ˜C₄ haloalkoxy group;

each of X² and X³ is independently one member selected from the groupconsisting of hydrogen atom, a C₁ ˜C₄ alkyl group and a C₁ ˜C₄ haloalkylgroup;

X⁴ is one member selected from the group consisting of hydrogen atom,halogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group and C₁ ˜C₄alkoxy group;

each of X⁵, X⁶, X⁷ and X⁸ is independently hydrogen atom or a C₁ ˜C₄alkyl group;

further, a combination of X² and X⁵ or a combination of X⁵ and X⁷ may bean unsaturated bond;

n is an integer of 0, 1 or 2;

p is an integer of 0 or 1; and

Q is hydrogen atom or any one of the following groups (a) to (h),##STR7##

In the groups (a) to (h), R³ is one member selected from the groupconsisting of a C₁ ˜C₈ alkyl group, a C₃ ˜C₈ cycloalkyl group and agroup of the general formula (V), ##STR8## in which Y is halogen atom,nitro group, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ alkoxy group and m is aninteger of 0, 1 or 2 or a C₁ ˜C₄ haloalkyl group,

R⁴ is one member selected from the group consisting of a C₁ ˜C₈ alkylgroup, a C₃ -C₈ cycloalkyl group, pyridyl group and a group of thegeneral formula (V),

R⁵ is hydrogen atom or a C₁ ˜C₄ alkyl group,

R⁶ is one member selected from the group consisting of hydrogen atom, aC₁ ˜C₄ alkyl group and a group of the general formula (V), and

each of R⁷ and R⁸ is independently hydrogen atom or a C₁ ˜C₄ alkylgroup, and

a salt thereof.

The second aspect of the present invention is directed to a herbicidecontaining the pyrazole derivative of the above general formula (I)and/or a salt thereof as active ingredient.

Further, the third aspect of the present invention is directed to anaromatic carboxylic acid derivative of the general formula (II) or asalt thereof, useful for the production of the pyrazole derivative ofthe general formula (I), ##STR9## wherein: X¹ is one member selectedfrom the group consisting of a C₁ ˜C₄ alkyl group, halogen atom, a C₁˜C₄ haloalkyl group, a C₂ ˜C₄ alkoxyalkyl, a C₁ ˜C₄ alkoxy group and aC₁ ˜C₄ haloalkoxy group;

each of X² and X³ is independently one member selected from the groupconsisting of hydrogen atom, a C₁ ˜C₄ alkyl group and a C₁ ˜C₄ haloalkylgroup;

X⁴ is one member selected from the group consisting of hydrogen atom,halogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group and a C₁˜C₄ alkoxy group;

each of X⁵,X⁶,X⁷ and X⁸ is independently one member selected from thegroup consisting of hydrogen atom and a C₁ ˜C₄ alkyl group;

further, a combination of X² and X⁵ or a combination of X⁵ and X⁷ may bean unsaturated bond;

p is an integer of 0 or 1; and

n is an integer of 0, 1 or 2.

PREFERRED EMBODIMENTS OF THE INVENTION

The novel pyrazole derivative of the present invention has the followinggeneral formula (I). ##STR10##

In the general formula (I), R¹ is hydrogen atom, a C₁ ˜C₄ alkyl group, aC₁ ˜C₄ haloalkyl group or a C₂ ˜C₄ alkoxyalkyl group, preferablyhydrogen atom or a C₁ ˜C₄ alkyl group. Specific examples of the C₁ ˜C₄alkyl group include methyl, ethyl, a propyl group such as n-propyl, anda butyl group such as n-butyl and i-butyl. The propyl group and thebutyl group may be linear, cyclic or branched. Methyl is preferred. TheC₁ ˜C₄ haloalkyl group is the same as the C₁ ˜C₄ alkyl group except thatat least one hydrogen atom of the C₁ ˜C₄ alkyl group is replaced with ahalogen atom (e.g., chlorine, fluorine, bromine or iodine), and the C₁˜C₄ haloalkyl group includes --CF₃, --C₂ F₅, --C₂ H₄ F, --CH₂ Cl,--CHF₂, --CCl₃, --C₂ H₃ Cl₂ and --C₂ H₃ F₂. Specific examples of the C₂˜C₄ alkoxyalkyl group include --CH₂ --OCH₃, --CH₂ --OC₂ H₅, --CH₂ --OC₃H₇, --CH(CH₃)OCH₃, --CH(CH₃)OC₂ H₅, --CH₂ CH₂ OCH₃ and --CH₂ CH₂ OC₂ H₅.

In the general formula (I), R² is a C₁ ˜C₄ alkyl group, a C₂ ˜C₄ alkenylgroup or a C₂ ˜C₄ haloalkenyl group, preferably a C₁ ˜C₄ alkyl group.Specific examples of the C₁ ˜C₄ alkyl group include methyl, ethyl,propyl and butyl. The propyl and the butyl may be linear, cyclic orbranched. Preferred are methyl and ethyl. Specific examples of the C₂˜C₄ alkenyl group include --CH═CH₂, --CH₂ --CH═CH₂ and --CH═CH--CH═CH₂.The C₂ ˜C₄ haloalkenyl group is the same as the above C₂ ˜C₄ alkenylgroup except that at least one hydrogen atom of the C₂ ˜C₄ alkenyl groupis replaced with a halogen atom (e.g., chlorine, fluorine, bromine oriodine).

In the general formula (I), X¹ is hydrogen atom, a C₁ ˜C₄ alkyl group, aC₁ ˜C₄ haloalkyl group, a C₂ ˜C₄ alkoxyalkyl group, halogen atom, a C₁˜C₄ alkoxy group or a C₁ ˜C₄ haloalkoxy group, preferably a C₁ ˜C₄ alkylgroup or halogen atom. Specific examples of the C₁ ˜C₄ alkyl group, theC₁ ˜C₄ haloalkyl group and the C₂ ˜C₄ alkoxyalkyl group include thosedescribed concerning R¹ or R². The C₁ ˜C₄ alkyl group is preferablymethyl or ethyl, more preferably methyl. Specific examples of thehalogen include chlorine, fluorine, bromine and iodine, and the halogenis preferably chlorine. Specific examples of the C₁ ˜C₄ alkoxy groupinclude methoxy, ethoxy, propoxy and butoxy, and the propoxy and thebutoxy may be linear, cyclic or branched. The C₁ ˜C₄ haloalkoxy group isthe same as the C₁ ˜C₄ alkoxy group except that at least one hydrogenatom of the C₁ ˜C₄ alkoxy group is replaced with a halogen atom (e.g.,chlorine, fluorine, bromine or iodine). Examples of the C₁ ˜C₄haloalkoxy group include --OCF₃, --OC₂ F₅, --OC₂ H₄ F, --OC₂ H₄ Cl,--OCHF₂, --OCH₂ F, --OCCl₃, --OC₂ H₃ Cl₂ and --OC₂ H₃ F₂.

Each of X² and X³ is independently hydrogen atom, a C₁ ˜C₄ alkyl groupor a C₁ ˜C₄ haloalkyl group. Specific examples of the C₁ ˜C₄ alkyl groupand the C₁ ˜C₄ haloalkyl group include those described concerning R¹.Specific examples of a combination of X² and X³ are as follows. When X²is hydrogen atom, X³ is hydrogen atom or a C₁ ˜C₄ alkyl group. Anotherspecific preferred combination is that each of X² and X³ isindependently a C₁ ˜C₄ alkyl group.

X⁴ is hydrogen atom, halogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄haloalkyl group or a C₁ ˜C₄ alkoxy group. Specific examples of thehalogen atom, the C₁ ˜C₄ alkyl group, the C₁ ˜C₄ haloalkyl group and theC₁ ˜C₄ alkoxy group include those described concerning X¹. X⁴ ispreferably hydrogen atom, halogen atom or a C₁ ˜C₄ alkyl group, morepreferably hydrogen atom, chlorine atom or methyl group. When p=0, theposition of X⁴ is the 6- or 7-position, preferably the 7-position, onthe benzo[b]thiophene ring. When p=1, the position of X⁴ is the 7- or8-position, preferably the 8-position, on the thiochroman ring.

Each of X⁵, X⁶, X⁷ and X⁸ is independently hydrogen atom or a C₁ ˜C₄alkyl group. Specific examples of the C₁ ˜C₄ alkyl group include thosedescribed concerning R¹. Preferred is hydrogen atom or methyl group.

A combination of X² and X⁵ or a combination of X⁵ and X⁷ may form anunsaturated bond.

Q is hydrogen or one of the following groups (a) to (h). ##STR11##

In the above groups (a) to (h), R³ is one member selected from the groupconsisting of a C₁ ˜C₈ alkyl group, a C₃ -C₈ cycloalkyl group and agroup of the general formula (V). ##STR12##

Examples of the above C₁ ˜C₈ alkyl group include methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl and octyl groups. When the number of carbonatoms is 3 or greater, the alkyl group may be linear or branched.Examples of the C₃ -C₈ cycloalkyl group include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

In the general formula (V), Y is halogen atom, nitro group, a C₁ ˜C₄alkyl group, a C₁ ˜C₄ alkoxy group or a C₁ ˜C₄ haloalkyl group. Thehalogen atom includes those described concerning X¹. Examples of the C₁˜C₄ alkyl group include those described concerning R¹. Examples of theC₁ ˜C₄ alkoxy group include those described concerning X¹. The C₁ ˜C₄haloalkyl group is the same as the C₁ ˜C₄ alkyl group describedconcerning R¹ except that a hydrogen atom of the C₁ ˜C₄ alkyl group isreplaced with a halogen atom, and specific examples of the C₁ ˜C₄haloalkyl group include --CH₂ F, --CHF₂, --CF₃, --CF₂ CF₃, --CCl₃ and--CH₂ CF₃.

m representing the number of Y is an integer of 0, 1 or 2.

R⁴ is one member selected from the group consisting of a C₁ ˜C₈ alkylgroup, a C₃ ˜C₈ cycloalkyl group, pyridyl group and a group of thegeneral formula (V). specific examples of the C₁ ˜C₈ alkyl group and theC₃ ˜C₈ cycloalkyl group include those described concerning R³.

R⁵ is hydrogen atom or a C₁ ˜C₄ alkyl group, and examples of the C₁ ˜C₄alkyl group include those described concerning R¹.

R⁶ is hydrogen atom, a C₁ ˜C₄ alkyl group or a group of the generalformula (V), and specific examples of the C₁ ˜C₄ alkyl group includethose described concerning R¹.

Each of R⁷ and R⁸ is independently hydrogen atom or a C₁ ˜C₄ alkylgroup, and specific examples of the C₁ ˜C₄ alkyl group include thosedescribed concerning R¹.

The substituent Q is preferably hydrogen atom or the following group.

As --SO₂ --R³ : ##STR13##

p is an integer of 0 or 1. When p is 1, the pyrazole derivative of thegeneral formula (I) represents a pyrazole derivative of the generalformula (Ix). ##STR14##

When p is 0, the pyrazole derivative of the general formula (I)represents a pyrazole derivative of the general formula (Iy). ##STR15##

In the general formula (I), n which is the number of oxygen is an:integer of 0, 1 or 2. That is, the compound (I) is sulfide when n is 0,sulfoxide when n is 1, and sulfone when n is 2.

The pyrazole derivative of the general formula (I) in which Q ishydrogen, i.e., a compound of the formula (Ia) ##STR16## can have thefollowing three structures due to tautomerism, and the pyrazolederivative of the present invention includes all of the abovestructures. ##STR17##

Further, the pyrazole derivative of the formula (Ia) is an acidicsubstance, and can be easily converted to a salt by treating it with abase. The pyrazole derivative of the present invention also includes thesalt. The base can be selected from known bases without any problem,while examples of the base include organic bases such as amines andanilines and inorganic bases such as sodium compounds and potassiumcompounds. The amines include monoalkylamine, dialkylamine andtrialkylamine. The alkyl group of the alkylamines is generally a C₁ ˜C₄alkyl group. The anilines include aniline, monoalkylaniline anddialkylaniline. The alkyl group of the alkylanilines is generally a C₁˜C₄ alkyl group. The sodium compounds include sodium hydroxide andsodium carbonate, and the potassium compounds include potassiumhydroxide and potassium carbonate.

The herbicide of the present invention contains the novel pyrazolederivative of the formula (I) and/or a salt thereof as an activeingredient. The herbicide can be prepared by mixing these compounds witha liquid carrier such as a solvent or a solid carrier such as a mineralfine powder, forming the mixture into the preparation form of a wettablepowder, an emulsifiable concentrate, a dust or granules. The herbicidecan be imparted with emulsifiability, dispersibility and spreadabilityby adding a surfactant when the herbicide is prepared.

When the herbicide of the present invention is used in the form of awettable powder, generally, a composition prepared by mixing 10 to 55%by weight of the pyrazole derivative and/or its salt of the presentinvention, 40 to 88% by weight of a solid carrier and 2 to 5% by weightof a surfactant can be used as a wettable powder. Further, when it isused in the form of an emulsifiable concentrate, generally, it can beprepared by mixing 20 to 50% by weight of the pyrazole derivative and/orits salt of the present invention, 35 to 75% by weight of a solvent and5 to 15% by weight of a surfactant.

On the other hand, when it is used in the form of a dust, generally, itcan be prepared by mixing 1 to 15% by weight of the pyrazole derivativeand/or its salt of the present invention, 80 to 97% by weight of a solidcarrier and 2 to 5% by weight of a surfactant. Further, when it is usedin the form of granules, the granules can be prepared by mixing 1 to 15%by weight of the pyrazole derivative and/or its salt of the presentinvention, 80 to 97% by weight of a solid carrier and 2 to 5% by weightof a surfactant.

The above solid carrier can be selected from mineral fine powders, andthe mineral fine powders include oxides such as diatomaceous earth andslaked lime, phosphates such as apatite, sulfates such as gypsum, andsilicates such as talc, pyroferrite, clay, kaolin, bentonite, acid clay,white carbon, powdered quartz and powdered silica.

The solvent is selected from organic solvents, and specific examples ofthe organic solvents include aromatic hydrocarbons such as benzene,toluene and xylene, chlorinated hydrocarbons such as o-chlorotoluene,trichloroethane and trichloroethylene, alcohols such as cyclohexanol,amyl alcohol and ethylene glycol, ketones such as isophorone,cyclohexanone and cyclohexenyl-cyclohexanone, ethers such as butylcellosolve, diethyl ether and methyl ethyl ether, esters such asisopropyl acetate, benzyl acetate and methyl phthalate, amides such asdimethylformamide, and mixtures of these.

Further, the surfactantcanbeselected from anionic, nonionic, cationicand amphoteric ones (amino acid and betaine).

In combination with the pyrazole derivative of the above general formula(I) and/or the salt thereof, the herbicide of the present invention maycontain, as active ingredients, other herbicidally active component asrequired. The "other" herbicidally active component can be selected fromknown herbicides such as phenoxy-, diphenyl ether-, triazine-, urea-,carbamate-, thiocarbamate-, acid anilide-, pyrazole-, phosphoric acid-,sulfonylurea- and oxadiazone-based herbicides. The other herbicidallyactive component can be properly selected from the above herbicides.

Further, the herbicide of the present invention may contain aninsecticide, a fungicide, a plant growth regulator and a fertilizer asrequired.

The pyrazole derivative of the formula (I), provided by the presentinvention, is produced by the following methods (1) and (2).

First, the method (1) of producing the pyrazole derivative of thepresent invention will be explained in detail. ##STR18##

In the above reaction scheme, is any one of the following groups (a) to(h). ##STR19##

In the above groups (a) to (h), R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as definedalready.

In the above reaction scheme, Hal bonding to Q¹ is a halogen atom.

In the above reaction scheme, R¹, R², X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, pand n are as defined already.

The above production method will be explained step by step hereinafter.

(Step 1)

A compound of the formula (II) and a compound of the formula (III) arereacted with each other in an inert solvent in the presence of adehydrating agent such as DCC (N,N'-dicyclohexylcarbodimimide), CDI(1,1-carbonyldiimidazole) or EDC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and a base, to produce apyrazole derivative of the formula (Ia).

The amount of the compound of the formula (III) is preferably 1.0˜3.0mol per mole of the compound of the formula (II). Further, the amount ofthe dehydrating agent is preferably 1.0˜1.5 mol per mole of the compoundof the formula (II). The base is not specially limited in kind, whilepotassium carbonate or sodium carbonate is preferred. The amount of thebase is preferably 0.5 to 2.0 mol per mole of the compound of theformula (II). The solvent for the reaction is not specially limited ifit is inert to the reaction. The solvent is preferably selected fromacetonitrile, 1,4-dioxane, t-amyl alcohol, t-butyl alcohol and i-propylalcohol. The reaction temperature can be selected from the range of from0° C. to the boiling point of the solvent, while it is preferably about80° C. The reaction time is 1˜48 hours, while it is generally about 8hours.

An ester is formed as a reaction intermediate, and this esterintermediate can be isolated by means such as silica gel columnchromatography, while the reaction is generally proceeded with withoutisolating the ester intermediate. When the ester intermediate isisolated, a base is added to the ester intermediate to further proceedwith the reaction, whereby the intended pyrazole derivative (Ia) can beobtained. The amount of the base used in this case is 0.5 to 3.0equivalents, preferably 0.5 to 1.5 equivalents, based on the esterintermediate. The reaction temperature is generally 80°˜150° C.,preferably 100°˜120° C. The reaction time is generally 0.5 to 8 hours,preferably approximately 1 to 2 hours.

After the completion of the reaction, according to a conventionalmethod, the solvent is distilled off, the residue is liquid-separatedwith an organic solvent and water, the aqueous layer is neutralized withan acid such as hydrochloric acid and extracted with ethyl acetate, theorganic layer is dried over a dehydrating agent such as anhydrous sodiumsulfate, and the solvent is distilled off, whereby the intended pyrazolederivative (Ia) can be obtained.

(Step 2)

The compound (Ia) obtained in step 1 is reacted with Q¹ -Hal (IV) (inwhich Q¹ and Hal are as defined already) in an inert solvent in thepresence of a base, to produce a compound (Id).

In this step, the compound (Ia):compound (IV) molar ratio is preferably1:1˜1:3. For collecting hydrogen halide byproducted by the reaction,preferably, a base such as sodium carbonate, potassium carbonate,triethylamine or pyridine is used in at least an equimolar amount basedon the starting material of the formula (Ia). The reaction temperatureis preferably set in the range of from room temperature to the boilingpoint of the solvent. The solvent used in the reaction includes aromatichydrocarbons such as benzene and toluene, ethers such as diethyl ether,ketones such as methyl ethyl ketone and halogenated hydrocarbons such asmethylene chloride and chloroform. A two-phase solvent consisting of theabove solvent and water may be also used. In this case, a more desirableresult can be obtained by adding a phase-transfer catalyst such as crownether or benzyltriethylammonium chloride to the reaction system.

After the completion of the reaction, according to a conventionalmethod, the reaction mixture is liquid-separated, the end product isextracted from the aqueous layer by means of an organic solvent such asdichloromethane, the organic layer is dehydrated and then solvent isdistilled off, whereby the intended pyrazole derivative (Id) can beisolated.

In the reaction above, the pyrazole compound represented by the formula(II) which is used as the reaction reagent can be synthesized by themethod disclosed in JP-A-61-257974.

In the above method, the compound of the general formula (III) isreacted with the aromatic carboxylic acid of the general formula (II),##STR20## wherein X¹ is one member selected from the group consisting ofa C₁ ˜C₄ alkyl group, halogen atom, a C₁ ˜C₄ haloalkyl group, a C₂ ˜C₄alkoxyalkyl group, a C₁ ˜C₄ alkoxy group and a C₁ ˜C₄ haloalkoxy group,

each of X² and X³ is independently one member selected from the groupconsisting of hydrogen atom, a C₁ ˜C₄ alkyl group and a C₁ ˜C₄ haloalkylgroup,

X⁴ is one member selected from the group consisting of hydrogen atom,halogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group and a C₁˜C₄ alkoxy group,

each of X⁵, X⁶, X⁷ and X⁸ is independently hydrogen atom or a C₁ ˜C₄alkyl group,

a combination of X² and X⁵ or a combination of X⁵ and X⁷ may form anunsaturated bond,

p is an integer of 0 or 1, and

n is an integer of 0, 1 o 2.

The above aromatic carboxylic acid of the general formula (II) is anovel compound disclosed in no literature, and it is useful as anintermediate for the production of the pyrazole derivative of thepresent invention.

Specific examples of X¹, X², X³, X⁴, X⁵, X⁶, X⁷ and X⁸ in the formula(II) include those described concerning the pyrazole derivative of theabove formula (I).

The aromatic carboxylic acid derivative of the formula (II) is an acidicsubstance, and can be easily converted to a salt by treating it with abase. This salt is also included in the aromatic carboxylic acidderivative of the present invention. The base can be selected from knownbases without any limitation. For example, the base includes organicbases such as amines and anilines and inorganic bases such as sodiumcompounds and potassium compounds. The amines include monoalkylamine,dialkylamine and trialkylamine. The alkyl group of the alkylamines isgenerally a C₁ ˜C₄ alkyl group. The anilines include aniline,monoalkylaniline and dialkylaniline. The alkyl group of the alkylalinesis generally a C₁ ˜C₄ alkyl group. The sodium compounds include sodiumhydroxide and sodium carbonate, and the potassium compounds includepotassium hydroxide and potassium carbonate.

The aromatic carboxylic acid derivative of the general formula (II) inwhich p is 1 (wherein X² and X⁵ do not bond to each other, nor do X⁵ andX⁷ bond to each other) can be produced by methods shown in the followingreaction schemes 1˜5. ##STR21## Production Scheme 1

Production scheme 1 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIx) in which X⁶ is hydrogen.##STR22##

In the above production scheme, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸ and Halare as defined above.

Thiophenol of the formula (VI)as a starting material can be obtained bya known method (e.g., "Shin-Jikken Kagaku Koza 14, Syntheses andReactions of Organic Compounds, III, page 1,704, chap. 8.1, Thiols, f.Synthesis through dithiocarbonate ester", Maruzen, issued Feb. 22,1986).

(Step 1)

The starting material of the formula (VI) and a compound of the formula(VII) are reacted with each other in an inert solvent such as acetone,diethyl ether or dimethylformamide in the presence of a base such asanhydrous potassium carbonate, sodium hydroxide, potassium hydroxide,anhydrous sodium carbonate or triethylamine, to obtain a compound of theformula (VIII). The compound of the formula (VII) and the base are usedin amounts of 1.0˜1.5 mol equivalent and 1.0˜1.5 mol equivalent,respectively, based on the starting material of the formula (VI).Generally, the reaction temperature is preferably approximately 0°˜80°C., and the reaction time is preferably approximately 1˜8 hours.

(Step 2)

The compound of the formula (VIII) is ring-closed or cyclized by addinga dehydration-condensation agent such as a polyphosphoric acid, sulfuricacid or phosphorus pentoxide to obtain a compound of the formula (IX)(thiochroman compound). The amount of the dehydration-condensation agentis 1˜10 mol equivalent based on the compound of the formula (VIII).Generally, the reaction temperature is preferably approximately 0°˜100°C., and the reaction time is preferably approximately 1˜8 hours.

(Step 3)

A halogenation reagent such as bromine, sulfuryl chloride or chlorine isreacted with the compound of the formula (IX) in the presence of asolvent such as methylene chloride, chloroform or carbon tetrachloride,to obtain a compound of the formula (X) in which a halogen issubstituted on the 6-position. Generally, the reaction temperature ispreferably approximately 0 °˜80° C., and the reaction time is preferablyapproximately 1˜80 hours.

(Step 4)

The compound of the formula (X) is reacted with magnesium (Mg) to form aGrignard reagent, and carbon dioxide (CO₂) is reacted therewith toobtain a compound (XI) (n=0, sulfide compound) which is an aromaticcarboxylic acid derivative of the formula (IIx) in which a carboxylgroup is introduced onto the 6-position, provided by the presentinvention. The solvent is preferably selected from ethers such asdiethyl ether and tetrahydrofuran. The reaction temperature ispreferably 0°˜70° C., particularly preferably 20°˜60° C. The reactiontime is generally approximately 1˜7 hours.

The amount of magnesium (Mg) for obtaining the Grignard reagent ispreferably 1.1˜3.5 mol equivalent based on the compound of the formula(X). The Grignard reaction is preferably carried out in the copresenceof alkyl iodide such as methyl iodide or alkyl bromide such as ethylbromide, since the reaction proceeds smoothly. The amount of thehalogenated alkyl used in this case is preferably 0.1˜2.5 mol equivalentbased on the compound of the formula (X).

The reaction between the Grignard reagent and carbon dioxide (CO₂) iscarried out by introducing carbon dioxide from a gas container into theGrignard reagent or by introducing carbon dioxide generated from dry ice(solid carbon dioxide) into the Grignard reagent. Dry ice may bedirectly added to the Grignard reagent for the reaction.

(Step 5)

An oxidizing agent (e.g., hydrogen peroxide, peracetic acid or sodiummetaperiodate) is reacted with the compound of the formula (XI) (acompound of the formula (IIx) in which n=0, sulfide compound) in asolvent (e.g., acetic acid, water or methanol), to obtain a compound(XII) (n=1, sulfoxide compound/n=2, sulfone compound) which is anaromatic carboxylic acid derivative of the formula (IIx) provided by thepresent invention. When the compound (XI) is reacted with 1 equivalentof the oxidizing agent, a sulfoxide (a compound (XII) in which n=1) isobtained. When the compound (XI) is reacted with 2 equivalents of theoxidizing agent, a sulfone (a compound (XII) in which n=2) is obtained.

Production Scheme 2

Production scheme 2 also shows a method of producing an aromaticcarboxylic acid derivative of the general formula (IIx) in which X⁶ ishydrogen. ##STR23## (Steps 1 and 2)

The steps 1 and 2 of producing a compound (IX) from a starting material(VI) through a compound (VIII) are the same as those in the productionof the compound (IX) from the compound (VI) in the scheme 1.

(Step 3)

A Lewis acid such as aluminum chloride, zinc chloride or iron chlorideor a proton acid such as hydrogen fluoride, sulfuric acid or phosphoricacid, and acetylchloride, are reacted with the compound of the formula(IX) in the presence of a solvent such as dichloromethane, nitromethane,acetonitrile or benzene, to obtain a compound (XIII) having an acetylgroup introduced onto its 6-position. The amount of the Lewis acid orthe proton acid is 1.0˜1.5 mol equivalent based on the compound of theformula (IX), and the amount of the acetyl chloride is 1.0˜1.5 molequivalent based on the compound of the formula (IX). Generally, thereaction temperature is preferably approximately 0°˜80° C., and thereaction time is preferably approximately 1˜8 hours.

(Step 4)

An oxidizing agent (e.g., hydrogen peroxide, peracetic acid or sodiummetaperiodate) is reacted with the compound (XIII) (sulfide) in asolvent (e.g., acetic acid, water or methanol), to obtain a compound(XIV) (n=1, sulfoxide compound/n=2, sulfone compound). When the compound(XIII) is reacted with 1 equivalent of the oxidizing agent, a sulfoxidecompound (a compound (XIV) in which n=1) is obtained. When the compound(XIII) is reacted with 2 equivalents of the oxidizing agent, a sulfonecompound (a compound (XIV) in which n=2) is obtained.

(Step 4')

The method of converting a methyl ketone group (acetyl group) on the6-position to a carboxyl group without oxidizing the sulfur atom S of athiochroman ring is disclosed in J. Am. Chem. Soc. 66, page 1,612(1944). That is, the methyl ketone compound of the formula (XIII) isreacted with iodine in pyridine and then decomposed with an alkali,whereby a compound (XI) (n=0, sulfide compound) which is an aromaticcarboxylic acid derivative of the formula (IIX) provided by the presentinvention is obtained.

(Step 5)

The methyl ketone compound (XIV) is converted to a compound (XII) (n=1,sulfoxide compound/n=2, sulfone compound) which is an aromaticcarboxylic acid derivative (IIx) of the present invention, by reactingthe methyl ketone compound (XIV) in a haloform reaction in the presenceof an oxidizing agent (e.g., permanganate, chromic acid, halogen, oxygenor sulfuric acid).

The aromatic carboxylic acid derivative of the general formula (IIx) canbe generally produced by the following production scheme 3.

Production Scheme 3 ##STR24## (Step 1)

Thiophenol of the formula (VI) is reacted with an alcohol of the formula(XV) in an aromatic solvent such as benzene or toluene or a halogenatedhydrocarbon solvent such as dichloroethane or tetrachloroethane in thepresence of an acid catalyst such as sulfuric acid, p-toluenesulfonicacid, methanesulfonic acid, formic acid or acetic acid, to obtain acompound of the formula (XVI). The amount of the alcohol of the formula(XV) is 1.0˜3.0 mol equivalent based on the thiophenol of the formula(VI). The amount of the acid catalyst is 0.01 to 1.0 mol equivalentbased on the thiophenol. Acetic acid or formic acid may be used as asolvent as well. The reaction temperature can be set in the range offrom room temperature to the boiling point of the solvent, while it isgenerally from 50° C. to 100° C.

(Step 2)

A Grignard reagent is reacted with the compound of the formula (XVI) toobtain an alcohol of the formula (XVII). The reaction in this step is awell-known Grignard reaction, and its details are omitted.

(Step 3)

This is a step in which a dehydrating agent such as polyphosphoric acid,diphosphorus pentoxide or sulfuric acid or an acid catalyst such asmethanesulfonic acid or p-toluenesulfonic acid is reacted with thealcohol of the formula (XVII) to produce a compound of the formula(XIX). As a solvent, there may be used as an aromatic hydrocarbon suchas benzene or toluene or a halogen-containing hydrocarbon solvent suchas dichloroethane or tetrachloroethane. Polyphosphoric acid or sulfuricacid may be also used as a solvent as well. The reaction temperature canbe set in the range of from room temperature to the boiling point of thesolvent, while it is generally from 50° C. to 100° C.

(Step 4)

This is a step in which a halogenating agent such as thionyl chloride,phosphorus oxychloride or phosphorus pentachloride is reacted with thealcohol of the formula (XVII), to obtain a halogen compound of theformula (XVIII). The amount of the halogenating agent is 1.0˜1.5 molequivalent based on the alcohol of the formula (XVII). The solvent isnot specially limited if it is inert to the reaction, while it isselected from those described in step 3. Thionyl chloride or phosphorusoxychloride may be used as a solvent. The reaction temperature can beset in the range of from room temperature to the boiling point of thesolvent, while it is generally from 60° C. to 80° C.

(Step 5)

This is a step in which a Lewis acid such as aluminum chloride, zincchloride or iron chloride is reacted with the halogen compound of theformula (XVIII), to produce a compound of the formula (XIX). Aluminumchloride is preferred. The amount of the Lewis acid is 1.0˜1.5 molequivalent based on the compound of the formula (XIX). As a solvent,preferred is a halogenated hydrocarbon solvent such as methylenechloride or dichloroethane. The reaction temperature can be set in therange of from 0° C. to the boiling point of the solvent, while thereaction generally proceeds smoothly around room temperature.

The compound of the formula (XIX) is produced by the above steps, andthe procedures thereafter are carried out in the same manner as inProduction scheme 1 or 2, to obtain an aromatic carboxylic acid of thegeneral formula (IIx).

Production scheme 4

Production scheme 4 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIx) in which both X³ and X⁵ arehydrogen. ##STR25## (Step 1)

A brominated thiochroman-4-one compound (XX) as a starting material canbe produced by a known method, for example, a method disclosed inJP-A-58-198483 and International Laid-open Patent PublicationWO88/06155. A Grignard reagent is reacted with the brominatedthiochroman-4-one compound of the formula (XX) to convert it into athiochromanol derivative of the formula (XXI). The reaction in this stepis a typical Grignard reaction and its details are omitted.

(Step 2)

This is a step in which the thiochromanol derivative of the formula(XXI) is dehydrated in an organic solvent in the presence of an acidcatalyst, to form 3,4-dehydrothiochroman derivative of the formula(XXII). The acid catalyst is selected from sulfuric acid,p-toluenesulfonic acid, methanesulfonic acid andtrifluoromethanesulfonic acid. The amount of the acid catalyst is0.001˜1.0 mol equivalent, preferably 0.01˜0.1 mol equivalent, based onthe thiochromanol derivative (XXI). The solvent includes aromatichydrocarbon solvents such as benzene and toluene and halogenatedhydrocarbon solvents such as 1,2-dichloroethane, 1,1,1-trichloroethaneor carbon tetrachloride. The reaction temperature is generally 60°˜120°C., preferably 80°˜100° C.

(Step 3)

This is a step in which the 3,4-dehydrothiochroman derivative of theformula (XXII) is reduced to form a thiochroman derivative of theformula (XXIII). The reduction method is not specially limited, whilethe reduction is preferably carried out with hydrogen in the presence ofa catalyst such as palladium or platinum under the conditions ofatmospheric pressure or elevated pressure.

Thereafter, the same carboxylation and oxidation as those in the aboveProduction scheme 1 are carried out to obtain an aromatic carboxylicacid of the general formula (IIx).

Production scheme 5

Production scheme 5 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIx) in which X⁵ is hydrogen.##STR26## (Step 1)

The step is a step wherein a thiophenol of the formula (VI) andα,β-unsaturated ketone of the formula (XXIV) are reacted with each otherin the presence of a basic catalyst such as pyridine, piperidine ortriethylamine to form a sulfide of the formula (XVIa). The solvent usedfor the reaction is not specially limited if it is inert to thereaction. Preferred is a halogenated hydrocarbon solvent such as1,2-dichloroethane, 1,1,1-trichloroethane or 1,1,2,2-tetrachloroethane.The reaction temperature can be set in the range of from roomtemperature to the boiling point of the solvent, while the reactiongenerally proceeds smoothly around room temperature. The amount of theα,β-unsaturated ketone of the formula (XXIV) is 1˜5 mol, preferably1.0˜1.5 mol per mole of the thiophenol of the formula (VI).

Steps 2˜5 hereinafter can be carried out in the same manner as in Scheme3, and their details are omitted. Then, a compound (XIXa) obtained inthe step 3 or 5 is reacted in the same manner as in the above Productionscheme 1 or 2, to obtain an aromatic carboxylic acid derivative of theformula (IIx).

Production scheme 6

Production scheme 6 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIx) in which both X² and X⁵ arehydrogen. ##STR27## (Step 1)

The step is a step wherein the sulfide of the formula (XVIa), obtainedin step 1 in the production scheme 5, is reduced to form an alcohol ofthe formula (XVIIb). The reducing agent for use is not much limited,while sodium borohydride is preferably used. The amount of the sodiumborohydride is 0.25˜1 mol equivalent based on the sulfide of the formula(XVIa). The solvent is preferably selected from alcohol solvents such asmethanol and ethanol. Generally, the reaction proceeds smoothly when thereaction temperature is in the range of from 0° C. to room temperature,and no heating is particularly required.

The steps 2, 3 and 4 thereafter can be carried out in the same manner asin the steps 3, 4 and 5 in Production scheme 3, and their details aretherefore omitted. Then, a compound (XIXb) obtained in the step 3 or 4is reacted in the same manner as in Production scheme 1 or 2, to obtainan aromatic carboxylic acid derivative of the formula (IIx).

An aromatic carboxylic acid derivative of the general formula (II) inwhich p is 0 (provided that X² and X⁵ do not bond to each other), i.e,an aromatic carboxylic acid derivative of the general formula (IIy), isproduced by any one of methods in the following Production scheme 7˜10.##STR28## Production scheme 7

Production scheme 7 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIy) in which X² is methyl.##STR29## (Step 1)

Step 1 is directed to a reaction in which a substituted thiphenol (VI)is reacted with a halogenated olefin (XXV) as an alkylating agent in thepresence of a base, to obtain an alkyl-substituted thiophenol (XXVI).

The base used in the above reaction is selected from inorganic basessuch as anhydrous potassium carbonate, sodium hydroxide and potassiumhydroxide and organic bases such as triethylamine, while preferred isanhydrous potassium carbonate. The amount of the base is generally0.5˜3.0 equivalents, preferably 1.0˜1.2 equivalents, based on thesubstituted thiophenol (VI).

The amount of the halogenated olefin (XXV) used as an alkylating agentin the above reaction is generally 1.0˜2.0 equivalents, preferably1.0˜1.2 equivalents, based on the substituted thiophenol (VI).

Any solvent is used for the reaction without any special limitation ifit is inert to the reaction, while acetone or dimethylformamide (DMF) ispreferred. The reaction time is 10 minutes˜8 hours, while it isgenerally completed in about 2 hours. The reaction temperature can beset in the range of 0° C.˜ the reflux temperature, while the range offrom room temperature to 60° C. is preferred.

After the completion of the reaction, the reaction mixture is cooled,insolubles are removed, and the solvent is distilled off. The residue isre-dispersed in an organic solvent such as hexane, washed and dried, andthe solvent is distilled off, whereby the alkyl-substituted thiophenol(XXVI) can be isolated.

(Step 2)

The step 2 is directed to a reaction for cyclizing the alkyl-substitutedthiophenol (XVII) by an intra-molecular Friedel-Crafts reaction in thepresence of a dehydration-condensation agent, to form ahydrobenzo[b]thiophene compound (XXVII).

The dehydration-condensation agent used in the above reaction isselected, for example, from sulfuric acid, phosphoric acid, phosphoruspentoxide and polyphosphoric acid, and polyphosphoric acid is preferred.The amount of the dehydration-condensation agent is generally 1˜10 molequivalent based on the alkyl-substituted thiophenol (XXVI).

The reaction temperature is in the range of from room temperature to200° C., while it is generally preferably 100° to 150° C. The reactiontime is 30 minutes to 16 hours, while it is generally preferably 2 to 8hours.

After the completion of the reaction, the reaction mixture is pouredinto ice water, a solvent such as hexane is added, and the mixture isliquid-separated. The resultant organic layer is washed and dehydrated,and then the solvent is distilled off. The resultant residue is purifiedby means such as column chromatography using a developer solvent such ashexane, whereby the hydrobenzo[b]thiophene compound (XXVII) can beisolated.

(Step 3)

The step 3 is directed to a reaction for obtaining a halogenatedbenzo[b]thiophene compound (XXVIII) in which a halogen is substituted onthe 5-position of the benzo[b]thiophene ring, by reacting thehydrobenzo[b]thiophene compound (XXVII) with a halogenating reagent suchas bromine, sulfuryl chloride or chlorine in the presence of a solventsuch as methylene chloride, chloroform or carbon tetrachloride.

The amount of the halogenating reagent used for the above reaction isgenerally 1.0˜3.0 equivalents, preferably 1.0˜1.5 equivalents, based onthe hydrobenzo[b]thiophene compound (XXVIII). Preferably, the reactiontemperature is generally 0°˜80° C., and the reaction time is generallyapproximately 1˜80 hours.

After the completion of the reaction, excessive halogenating reagent isremoved with a sodium hydrogensulfite aqueous solution and the residueis worked up according to a conventional method, whereby the intendedhalogenated benzo[b]thiophene compound (XXVIII) can be isolated.

(Step 4)

The step 4 is directed to a reaction for obtaining an aromaticcarboxylic acid derivative of the formula (IIy) in which a carboxylgroup is introduced onto the 5-position of a hydrobenzo[b]thiophenering, a compound (XXIX) (n=0, sulfide compound), by reacting thehalogenated benzo[b]thiophene (XXVIII) with magnesium (Mg) to form aGrignard reagent and reacting the Grignard reagent with carbon dioxide(CO₂). It is preferred to use an ether such as diethyl ether ortetrahydrofuran as a solvent. The reaction temperature is 0°˜70° C.,particularly preferably 20°˜60° C. The reaction time is generallyapproximately 1˜7 hours.

The amount of magnesium (Mg) for obtaining the Grignard reagent ispreferably 1.1˜3.5 mol equivalent based on the halogenatedhydrobenzo[b]thiophene compound (XXVIII). The Grignard reaction ispreferably carried out in the co-presence of alkyl iodide such as methyliodide or alkyl bromide such as ethyl bromide, since the reactionproceeds smoothly. The amount of the alkyl halide used in this case ispreferably 0.1˜2.5 mol equivalent based on the halogenatedhydrobenzo[b]thiophene compound (XXVIII).

The reaction between the Grignard reagent and carbon dioxide (CO₂) iscarried out by introducing carbon dioxide gas from a gas container intothe Grignard reagent in a solvent or by introducing carbon dioxide gasgenerated from dry ice (solid carbon dioxide). The reaction may becarried out by adding dry ice directly to the Grignard reagent.

After the reaction, an acid such as hydrochloric acid is added to thereaction mixture to terminate the reaction, the reaction mixture isliquid-separated by adding an organic solvent such as ethyl acetate, theresultant organic layer is liquid-separated by adding an alkali such asa potassium carbonate aqueous solution, and the resultant aqueous layeris neutralized with an acid such as hydrochloric acid and extracted withan organic solvent such as ethyl acetate. The resultant organic layer iswashed and dried and then the solvent is distilled off, whereby thearomatic carboxylic acid derivative of the formula (IIy), a compound(XXIX) (n=0, sulfide), can be isolated.

(Step 5)

The step 5 is directed to a reaction for obtaining an aromaticcarboxylic acid derivative of the formula (IIy), a compound (XXX)(n=1,sulfoxide, n=2, sulfone), by reacting an oxidizing agent (e.g., hydrogenperoxide, peracetic acid or sodium metaperiodate) with the compound ofthe formula (XXIX) in a solvent (e.g., acetic acid, water or methanol).

When the oxidizing agent in an amount of 1 equivalent based on thecompound (XXIX) is reacted, a sulfoxide (a compound of the formula (IIy)in which n=1) is obtained. When the oxidizing agent in an amount of atleast 2 equivalents based on the compound (XXIX) is reacted, a sulfone(a compound of the formula (IIy) in which n=2) is obtained.

In the above reaction, the reaction temperature is generally 25°˜110°C., preferably 60°˜100° C. The reaction time is generally 30 minutes˜8hours, preferably 1˜3 hours.

After the completion of the reaction, the reaction mixture is pouredinto a sodium hydrogensulfite aqueous solution and the mixture isliquid-separated by adding an organic solvent such as ethyl acetate. Theresultant organic layer is washed and dried, and then the solvent isdistilled off, whereby the intended compound of the formula (XXX) can beisolated.

Production scheme 8

The production scheme 8 also shows a method of producing an aromaticcarboxylic acid derivative of the general formula (IIy) in which X² ismethyl. ##STR30##

A hydrobenzo[b]thiophene compound of the formula (XXVII) as a startingmaterial is obtained by steps 1 and 2 in Production scheme 7. Reactionsin steps 1, 2, 2' and 3 are essentially the same as those in steps 3, 4,4' and 5 in Production scheme 2, and their details are thereforeomitted.

Production scheme 9

Production scheme 9 shows a method of producing an aromatic carboxylicacid derivative of the general formula (IIy) in which both X² and X⁶ arehydrogen. ##STR31## (Step 1)

The step 1 is directed to a reaction for obtaining a compound of theformula (XXXIV) by condensing the substituted thiophenol (VI) and anα-halo-carbonyl compound (XXXIII) in the presence of a base.

The base used in the above reaction is selected from inorganic basessuch as anhydrous potassium carbonate, sodium hydroxide and potassiumhydroxide and organic bases such as triethylamine. Anhydrous potassiumcarbonate is preferred. The amount of the base is generally 0.5˜3.0 molequivalent, preferably 1.0˜1.2 mol equivalent, based on the substitutedthiophenol.

The amount of the α-halo-carbonyl compound (XXXIII) is generally 1.0˜2.0mol equivalent, properly 1.0˜1.2 mol equivalent, based on thesubstituted thiophenol (VI).

Any solvent can be used without any special limitation if it is inert tothe reaction, while it is proper to use acetone or dimethylformamide(DMF).

The reaction temperature can be set in the range of from 0° C. to thereflux temperature of the solvent, while the range of from roomtemperature to 60° C. is preferred. The reaction time is 10 minutes to 8hours, while the reaction is generally completed in about 2 hours.

After the completion of the reaction, the reaction mixture is cooled,insolubles are removed and the solvent is distilled off. The resultantresidue is re-dispersed in a solvent such as hexane, washed and dried,and the solvent is distilled of, whereby the compound (XXXIV) can beisolated.

(Step 2)

The step 2 is directed to a reaction for forming a benzo[b]thiophenecompound (XXXV) by subjecting the compound (XXXIV) obtained in step 1 toan intra-molecular dehydration-condensation reaction in the presence ofa dehydrating agent and/or an acid catalyst.

The dehydrating agent used in the above reaction includes sulfuric acid,phosphoric acid, phosphorus pentoxide and polyphosphoric acid, andpolyphosphoric acid is preferred. The acid catalyst includesp-toluenesulfonic acid, methanesulfonic acid andtrifluoromethanesulfonic acid, and trifluoromethanesulfonic acid ispreferred. The amount of the dehydrating agent and/or the acid catalystis generally 1˜10 mol equivalent, preferably 1.0˜3.0 mol equivalent,based on the compound (XXXIV).

The reaction temperature can be set in the range of from 0° C. to thereflux temperature of the solvent, while the range of from roomtemperature to 60° C. is generally preferred. The reaction time is 10minutes to 8 hours, while the reaction is generally completed in about 2hours.

After the completion of the reaction, according to a conventionalmethod, the reaction mixture is poured into ice water, a precipitatedwhite crystal is re-dispersed in an organic solvent such as n-hexane,the dispersion is washed and the then solvent is distilled off, wherebythe benzo[b]thiophene compound (XXXV) can be isolated.

(Step 3)

The step 3 is directed to a reaction for obtaining ahydrobenzo[b]thiophene compound (XXVIIa) in which a double bond betweenthe 2- and 3-positions of the thiophene ring is reduced, by reducing thebenzo[b]thiophene compound (XXXV) obtained in step 2.

The method of the above reduction is not specially limited, while amethod of the reduction with hydrogen in the presence of a catalyst suchas palladium or platinum oxide under atmospheric pressure or elevatedpressure is facile and preferred.

After the completion of the reaction, according to a conventionalmethod, the catalyst is removed, and the solvent is distilled off,whereby the intended hydrobenzo[b]thiophene compound (XXVIIa) can beisolated.

A halogenation, a Grignard reaction and an oxidation thereafter can beaccomplished in the same manner as in the steps 3, 4 and 5 in Productionscheme 7, whereby the intended aromatic carboxylic acid derivative (IIy)can be obtained.

The aromatic carboxylic acid derivative of the general formula (IIy) canbe generally produced by the method in the following Production scheme10.

Production scheme 10 ##STR32## (Step 1)

A thiophenol of the formula (VI) and a ketone of the formula (XXXIIIa)are reacted with each other in the same manner as in the aboveProduction scheme 9, to produce a sulfide of the formula (XXXIVa).

(Step 2)

This is a step in which a Grignard reagent is reacted with the sulfideof the formula (XXXIVa) obtained in step 1, to form an alcohol of theformula (XXXVI). The reaction in this step is a typical Grignardreaction, and its details are therefore omitted.

Steps 3, 4 and 5 thereafter can be carried out in the same manner as inthe steps 3, 4 and 5 in Production scheme 4, and their details aretherefore omitted. The procedures thereafter are carried out in the samemanner as in the above Production scheme 7, to obtain the aromaticcarboxylic acid derivative of the formula (IIy).

The aromatic carboxylic acid derivative of the general formula (II) inwhich X⁴ is hydrogen can be produced by the following Production scheme11.

Production Scheme 11 ##STR33## (Steps 1 and 2)

These are steps in which the starting material of the formula (XXXVIII)obtained in the steps 1˜3 in Production scheme 1 or in the steps 1˜3 inProduction scheme 4 or 7 are treated in the same manner as in the steps4 and 5 in Production scheme 1 through an aromatic carboxylic acidderivative of the formula (XXXIX) (n=0, sulfide compound), to form anaromatic carboxylic acid derivative of the formula (XXXX) (n=1, sulfonecompound/n=2, sulfoxide compound). For details of these reactions, seethe explanation of Production scheme 1.

(Step 3)

This is a step in which the compound of the formula (XXXX) is reduced toform an aromatic carboxylic acid derivative of the formula (XXXXI) (n=1or 2). The reduction method is not specially limited. For example, thereis a method in which the reduction is carried out with hydrogen havingatmospheric pressure or elevated pressure in the presence of a catalystsuch as palladium or platinum oxide, or it is directly carried out inthe presence of zinc powder without using a catalyst. For acceptinghydrogen chloride formed in the reaction, a base such as triethylamine,pyridine, sodium hydroxide or potassium hydroxide is allowed to beco-present in an amount equal to or greater than the equivalent weightbased on the compound of the formula (XXXX). As a solvent, it ispreferred to use an alcohol solvent such as methanol or ethanol. Forfully dissolving the starting material, it is preferred to use ethanolhaving a water content of about 60%. The reaction temperature isgenerally 20°˜120° C., and the reaction time is generally approximately1˜12 hours.

An aromatic carboxylic acid derivative of the formula (II) in which p is1 and X² and X⁵ together form a bond, i.e., a compound of the formula(IIza), is produced by the following Production scheme 12 or 13.##STR34## Production Scheme 12 ##STR35## (Step 1)

This is a step in which a benzoic acid ester of the formula (XXXXII) anda mercaptopropionic acid derivative of the formula (XXXXIII) aresubjected to a condensation reaction to form a phenythiopropionic acidderivative of the formula (XXXXIV). This step is preferably carried outin an aprotic polar solvent such as N-methylpyrrolidone orN,N-dimethylformamide in the presence of a base. The base includespotassium carbonate and sodium carbonate. The amount of the base is1.0˜3.0 mol equivalent based on the benzoic acid ester. The reactiontemperature can be set in the range of from room temperature to theboiling point of the solvent, while it is preferably 80° C. to 130° C.The reaction time is generally 1˜8 hours.

(Step 2)

This is a step in which the phenylthiopropionic acid derivative (XXXXIV)obtained in step 1 is condensed and cyclized to form a thiochroman-4-onederivative of the formula (XXXXV).

The condensation method includes (i) a method in which thephenylthiopropionic acid derivative (XXXXIV) is dehydrated and cyclizedin the presence of an acid catalyst such as hydrogen fluoride, sulfuricacid, phosphorus pentachloride, phosphoric acid, polyphosphoric acid,tin chloride, zinc chloride, aluminum chloride or Amberlite (trade nameof an ion-exchange resin) and (ii) a method in which thephenylthiopropionic acid derivative (XXXXIV) is reacted with achlorinating agent such as thionyl chloride to form an acid chloride andthe acid chloride is cyclized in the presence of an acid catalystsimilar to those used in the above method (i). The solvent used for thereaction is not specially limited if it is inert under reactionconditions, and it is preferably selected from hydrocarbon solvents suchas pentane and hexane and halogen-containing solvents such asdichloromethane and 1,2-dichloroethane. It is also preferred to usepolyphosphoric acid as both a solvent and an acid catalyst. In the abovecondensation cyclization method (i), the amount of the acid catalyst is0.01˜20 mol equivalent, preferably 1.0˜10 mol equivalent, based on thephenylthiopropionic acid derivative (XXXXIV). The reaction temperatureis generally in the range of from room temperature to 120° C., while itis preferably 50˜100° C. The reaction time is generally 30 minutes˜8hours, while it is preferably 30 minutes to 2 hours. In the abovecondensation cyclization method (ii), the amount of the chlorinatingagent is 1.0˜3.0 mol equivalent, preferably 1.1˜1.5 mol equivalent,based on the phenylthiopropionic acid derivative (XXXXIV). The reactiontemperature for the chlorination is generally in the range of from 0° to120° C., preferably 30 minutes to 2 hours. The amount of the acidcatalyst used in the cyclization method (ii) is 0.01˜1.0 mol equivalent,preferably 0.1˜1.0 mol equivalent, based on the acid chloride. Thetemperature for the reaction in the presence of the acid catalyst isgenerally room temperature to 120° C., preferably room temperature to80° C. The reaction time is generally 30 minutes to 8 hours, preferably2 to 4 hours.

(Step 3)

This is a step in which the thiochroman-4-one derivative (XXXXV)obtained in step 2 is reduced to obtain a hydroxythiochroman derivativeof the formula (XXXXVI).

The reduction method is not specially limited, and for example, thereduction is carried out (i) by a method using a reducing agent such assodium borohydride in a solvent inert to the reaction such as an alcoholor dichloromethane or (ii) by a method of hydrogenation underatmospheric pressure or elevated pressure in the presence of a reducingcatalyst such as palladium or nickel. In the above reduction method (i),the amount of the reducing agent is 1.0˜5.0 mol equivalent, preferably1.1˜2.0 mol equivalent, based on the thiochroman-4-one derivative(XXXXV). The reaction temperature is generally -20°˜50° C., preferably0°˜20° C. The reaction time is generally 30 minutes to 8 hours,preferably 30 minutes to 2 hours. In the above reduction method (ii),the amount of the reducing catalyst is 1˜50% by weight, preferably10˜20% by weight, based on the thiochroman-4-one derivative (XXXXV). Thepressure of the hydrogen is generally atmospheric pressure˜100 kg/cm²,preferably 10˜50 kg/cm². The reaction temperature is room temperature to100° C., and the reaction time is 1 to 8 hours.

In a preferred embodiment of the step 3, the reduction is carried out ina solvent such as ethanol or dichloroethane in the presence of sodiumborohydride. In this preferred embodiment, preferably, the reactiontemperature is 0° C. to room temperature and the reaction time is 30minutes to 2 hours.

When the reduction is carried out in the presence of sodium borohydride,the reaction mixture after the completion of the reaction is poured intoice water, and dichloromethane is added for extraction. The resultantorganic layer is washed with a saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate and the solvent isdistilled off, to give a crude product. The crude product is can bedirectly fed to the subsequent reaction without its purification.

(Step 4)

The step 4 is a step in which the hydroxythiochroman derivative (XXXXVI)obtained in step 3 is oxidized to obtain hydroxythiochroman oxide(XXXXVII), while this oxidation is basically the same as the oxidationin the step 5 in the Production scheme 1 and can be carried outaccording thereto. Details of this oxidation are therefore omitted.

(Step 5)

The step 5 is a step in which the hydroxythiochroman oxide (XXXXVII)obtained in step 4 is dehydrated to obtain a 3,4-dehydrothiochroman(XXXXVIII), while this dehydration is basically the same as thedehydration in the step 2 in the Production scheme 4 and can be carriedout according thereto. Details of this dehydration are thereforeomitted.

(Step 6)

The step 6 is a step in which the 3,4-dehydrothiochroman (XXXXVIII)obtained in step 5 is hydrolyzed to obtain the intended aromaticcarboxylic acid (IIza, X³ =hydrogen). This hydrolysis is well knownhydrolysis of an ester, and its details are therefore omitted. This step6 may be carried out prior to step 4 or step 5.

Production Scheme 13 ##STR36##

The compound of the general formula (XXII) as a starting material isobtained by the step 1 and the step 2 in Production scheme 4. The steps1 and 2 thereafter are essentially the same as step 4 or 5 in Productionscheme 1 and the detailed explanation thereof is omitted.

An aromatic carboxylic acid derivative of the formula (II) in which p is0 and X² and X⁵ together form a bond, i.e., a compound of the formula(IIzb), is produced by the following Production scheme 14. ##STR37##Production Scheme 14 ##STR38##

As a starting material, a bromine-substituted thiophenol derivative ofthe formula (VI-Br) is used in place of the substituted thiophenol ofthe formula (VI) in Production scheme 9. The bromine-substitutedthiophenol derivative is also obtained by a known method similar to themethod of producing the substituted thiophenol.

The subsequent steps 1 and 2 are essentially the same as the steps 1 and2 in Production scheme 9, and the steps 3 and 4 are the same as the step4 or 5 in Production scheme 7. Their details are therefore omitted.

The novel pyrazole derivative of the formula (I) in which p is 1 andboth X² and X⁵ are hydrogen, provided by the present invention, i.e., apyrazole derivative of the general formula (If) or (Ig), is alsoobtained by the following method. ##STR39## (Step 1)

This is a step in which a pyrazole derivative of the formula (Ie) isreduced to form a pyrazole derivative (If) of the present invention. Thereduction is preferably carried out by a method using hydrogen havingatmospheric pressure or elevated pressure in the presence of a catalystsuch as palladium or platinum oxide. The amount of the catalyst is 5˜20%by weight based on the pyrazole derivative of the formula (Ie). As asolvent, it is preferred to use an alcohol such as methanol or ethanol.The reaction temperature is from room temperature to about 80° C., whilethe reaction generally smoothly proceeds at room temperature. Thereaction time is approximately 2 hours to 24 hours.

(Step 2)

The step 2 is a step in which a pyrazole derivative (Ig) is obtained byreacting the pyrazole derivative (If) with Q¹ -Hal. This step 2 isbasically the same as the step 2 in the method (1) of producing apyrazole derivative, to which please refer for details.

The 5-hydroxypyrazole of the general formula (III) as a startingmaterial for the production of the pyrazole derivative (I) of thepresent invention can be produced by one of the following methodsdepending upon its substituent. In the following reaction schemes, R¹and R² are as defined in the general formula (I). ##STR40##

The above (1)˜(3) show a method of producing 5-hydroxypyrazole of thegeneral formula (III) in which R² =hydrogen atom.

The above (4) and (5) show a method of producing 5-hydroxypyrazole ofthe general formula (III) in which R² =C₁ ˜C₄ alkyl group, C₁ ˜C₄haloalkyl group or C₂ ˜C₄ alkoxyalkyl group.

EXAMPLES

The present invention will be explained further in detail with referenceto Examples hereinafter, while the present invention shall not belimited to these Examples.

Intermediate Preparation Example 1

4,4,5,8-Tetramethylthiochroman-6-carboxylic acid-1,1-dioxide used inPreparation Example 1 to be described later was prepared in thefollowing steps. ##STR41## Step (1)

80 ml of acetone, 9.1 g (0.06 mol) of 1-bromo-3-methyl-2-butene and 8.0g (0.058 mol) of anhydrous potassium carbonate were added to 8.0 g(0.058 mol) of 2,5-dimethylthiophenol, and the mixture was refluxedunder heat for 1 hour. After the completion of the reaction, a formedsalt was removed by filtration, and the acetone was distilled off underreduced pressure. Then, ethyl acetate was added to the residue, and themixture was washed with a saturated sodium chloride aqueous solution.The mixture was dried over anhydrous sodium sulfate, and then theethylacetate was distilled off to give 12 g (yield 100%) of2-methyl-4-(2,5-dimethylphenyl)thio-2-butene.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.60(3H,s), 1.70(3H,s), 2.30(6H,s), 3.50(2H,d),5.15˜5.50(H,m), 6.80˜7.10(3H,m)

Step (2)

7.0 Grams (0.034 mol) of 2-methyl-4-(2,5-dimethylphenyl)thio-2-butenewas added to 51 g of polyphosphoric acid with stirring. The mixture wasfurther stirred at room temperature for 30 minutes, and the reactionmixture was poured into ice water and extracted with n-hexane. Anorganic layer was washed with a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. The n-hexane wasdistilled off under reduced pressure to give 6.7 g (yield 95%) of4,4,5,8-tetramethylthiochroman.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.40(6H,s), 1.95˜2.15(2H,m), 2.20(3H,s), 2.50(3H,s),2.80˜3.10(2H,m), 6.80(2H,dd)

Step (3)

100 ml of methylene chloride was added to 13.2 g (0.064 mol) of4,4,5,8-tetramethylthiochroman, 10.2 g (0.064 mol) of bromine wasdropwise added at room temperature, and then the mixture was allowed toreact for 2 hours. After the completion of the reaction, 70 ml of a 2%sodium hydrogensulfite aqueous solution was added, excessive bromine wasremoved, and the reaction mixture was liquid-separated. An organic layerwas washed with a saturated sodium hydrogencarbonate aqueous solutionand with a saturated sodium chloride aqueous solution, and dried overanhydrous sodium sulfate. The methylene chloride was distilled off underreduced pressure, and the resultant oily substance was purified bysilica gel column chromatography to give 15.9 g (yield 87%) of4,4,5,8-tetramethyl-6-bromothiochroman.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.45(6H,s), 1.90˜2.10(2H,m), 2.20(3H,s), 2.50(3H,s),2.80˜3.00(2H,m), 7.20(H,s)

Step (4)

2.9 Grams (0.12 mol) of magnesium was dispersed in 100 ml of THF(tetrahydrofuran), and 7.4 g (0.068 mol) of ethyl bromide was dropwiseadded. The mixture was allowed to react for 10 minutes, and then asolution of 9.7 g (0.034 mol) of 4,4,5,8-tetramethyl-6-bromothiochromanin THF was gradually added at room temperature. The reaction mixture wasrefluxed for 3 hours, and then cooled to 10° C., and carbon dioxide gaswas bubbled for 1 hour. Unreacted magnesium was dissolved by adding 100ml of 5% hydrochloric acid to the reaction mixture. THF was distilledoff under reduced pressure, methylene chloride was added, and an aqueouslayer was removed. An organic layer was extracted with a 5% potassiumcarbonate aqueous solution and adjusted to a pH of 1 by adding 5%hydrochloric acid. A formed solid was recovered by filtration, to give7.4 g (yield 88%) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.50(6H,s), 1.90˜2.10(2H,m), 2.25(3H,s), 2.70(3H,s),2.90˜3.10(2H,m), 7.55(H,s)

I.R. (KBr tablet, cm⁻¹): 3,450˜2,550, 2,980, 2,930, 1,695

m.p.: 166.0°˜167.1° C.

Step (5)

4 ml of acetic acid was added to 5 g (0.02 mol) of4,4,5,8-tetramethylthiochroman-6-carboxylic acid, further, 6.9 g (0.06mol) of a 30% hydrogen peroxide aqueous solution was added, and themixture was heated at 80° C. for 2 hours. 50 ml of a 2% sodiumhydrogensulfite aqueous solution was added to the reaction mixture, anda precipitated solid was recovered by filtration to give 5.1 g (yield90%) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.60(6H,s), 2.25˜2.50(2H,m), 2.65(3H,s), 2.75(3H,s),3.30˜3.50(2H,m), 7.55(H,s)

I.R. (KBr tablet, cm⁻¹): 3,500˜2,550, 3,000, 2,950, 1,630, 1,290, 1,130

m.p.: 208.8°˜209.3° C.

Intermediate Preparation Example 2

4,4,5-Trimethylthiochroman-6-carboxylic acid-1,1-dioxide used inPreparation Example 2 to be described later was prepared in thefollowing steps. ##STR42## Step (1)

0.63 Gram (0.026 mol) of magnesium was dispersed in 30 ml of THF, and1.89 g (0.0173 mol) of ethyl bromide was dropwise added. The mixture wasallowed to react for 10 minutes, and then a solution of 1.76 g (0.0058mol) of 4,4,5-trimethyl-6-bromo-8-chlorothiochroman in THF was graduallyadded at room temperature. The reaction mixture was refluxed for 7hours, and then cooled to 10° C., and carbon dioxide gas was bubbled for1 hour. Unreacted magnesium was dissolved by adding 30 ml of 5%hydrochloric acid to the reaction mixture. THF was distilled off underreduced pressure, ethyl acetate was added, and an aqueous layer wasremoved. An organic layer was extracted with a saturated sodiumbicarbonate aqueous solution and adjusted to a pH of 1 by adding 5%hydrochloric acid, and a formed solid was recovered by filtration, togive 0.54 g (yield 40%) of4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.50(6H,s), 1.90˜2.10(2H,m), 2.60(3H,s),2.85˜3.10(2H,m), 7.55(H,s)

I.R. (KBr tablet, cm⁻¹): 3,450˜2,550, 2,980, 2,930, 1,695

Step (2)

10 ml of acetic acid was added to 0.82 g (3.0 mmol) of4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid, 0.82 g (7.5 mmol)of a 30% hydrogen peroxide aqueous solution was further added, and themixture was heated at 80° C. for 3 hours. The reaction mixture waspoured into 100 ml of icewater, and was extracted with ethyl acetate. Anorganic layer was washed with a saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. The ethyl acetate wasdistilled off under reduced pressure to give 0.88 g (yield 96%) of4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.60(6H,s), 2.25˜2.50(2H,m), 2.65(3H,s),3.3˜3.50(2H,m), 7.60(H,s)

I.R. (KBr tablet, cm⁻¹): 3,500˜2,550, 3,000, 2,950, 1,630, 1,290, 1,130

Step (3)

0.88 Gram (2.90 mmol) of4,4,5-trimethyl-8-chlorothiochroman-6-carboxylic acid-1,1-dioxide wasdissolved in ethanol having a water content of 60%, 0.55 g (8.70 mmol)of a zinc powder was added, and the mixture was refluxed under heat for5 hours. After the completion of the reaction, 50 ml of water was added,the zinc powder was removed by filtration, and the remainder wasextracted with ethyl acetate. The extract was washed with a saturatedsodium chloride aqueous solution and dried over anhydrous sodiumsulfate. The ethyl acetate was distilled off under reduced pressure togive 0.60 g (yield 78%) of 4,4,5-trimethylthiochroman-6-carboxylicacid-1,1-dioxide.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.60(6H,s), 2.30˜2.50(2H,m), 2.75(3H,s),3.30˜3.50(2H,m), 7.90(2H,dd)

Intermediate Preparation Example 3

5,8-Dichloro-4,4-dimethylthiochroman-6-carboxylic acid-1,1-dioxide usedin Preparation Example 3 to be described later was prepared in thefollowing steps. ##STR43## Step (1)

1.26 Grams (9.45 mmol) of anhydrous aluminum chloride was suspended in10 ml of methylene chloride, and a solution of 0.74 g (9.45 mmol) ofacetyl chloride in 5 ml of methylene chloride was dropwise added withcooling with ice. The mixture was stirred until the reaction mixture washomogeneous, then, a solution of 1.95 g (7.88 mmol) of5,8-dichloro-4,4-dimethylthiochroman in 5 ml of methylene chloride wasadded, and the mixture was allowed to react at room temperature for 1hour. After the completion of the reaction, the reaction mixture waspoured into ice water and extracted with methylenechloride. An organiclayer was washed with a saturated sodium chloride aqueous solution anddried over anhydrous sodium sulfate. The methylene chloride wasdistilled off under reduced pressure, and the resultant oily substancewas purified by silica gel column chromatography to give 1.27 g (yield56%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.60(6H,s), 1.95˜2.30(2H,m), 2.55(3H,s),2.80˜3.10(2H,m), 7.15(H,s)

Step (2)

1 ml of acetic acid was added to 1.22 g (4.22 mmol) of6-acetyl-5,8-dichloro-4,4-dimethylthiochroman, 1.43 g (12.66mmol) of a30% hydrogen peroxide aqueous solution was further added, and themixture was heated at 80° C. for 2 hours. To the reaction mixture wasadded 10 ml of a 2% sodium hydrogensulfite, and a precipitated solid wasrecovered by filtration to give 0.96 g (yield 71%) of6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.65(6H,s), 2.30˜2.50(2H,m), 2.55(3H,s),3.35˜3.55(2H,m), 7.30(H,s)

I.R. (KBr tablet, cm⁻¹): 3,200˜2,700, 1,700, 1,300, 1,130

m.p.: 154.3°˜155.1° C.

Step (3)

1.04 Grams (26.1 mmol) of sodium hydroxide was dissolved in 20 ml ofwater, and 0.5 ml (8.7 mol) of bromine was added. Further, 0.93 g (2.9mmol) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide wasadded, and the mixture was stirred for 3 hours. Then the mixture washeated at 100° C. for 5 hours. After the completion of the reaction,ethyl acetate was added, the mixture was liquid-separated, andhydrochloric acid was added to an aqueous layer to adjust the aqueouslayer to a pH of 1. The extraction of the aqueous layer was carried outby adding ethyl acetate, and an organic layer was dried over anhydroussodium sulfate. The ethyl acetate was distilled off under reducedpressure to give 0.84 g (yield 90%) of5,8-dichloro-4,4-dimethylthiochroman-6-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deuteroacetone, internal standard:tetramethylsilane): 1.70(6H,s), 2.30˜2.50(2H,m), 3.40˜3.60(2H,m),7.75(H,s)

I.R. (KBr tablet, cm⁻¹): 3,500˜2,500, 1,750, 1,300, 1,130

Intermediate Preparation Example 4

5-Chloro-4,4,8-trimethyl-thiochroman-6-carboxylic acid-1,1-dioxide usedin Preparation Example 29 to be described later was prepared in thefollowing steps. ##STR44## Step (1)

3.2 Grams (24 mmol) of anhydrous aluminum chloride was suspended in 20ml of methylene chloride, and a solution of 1.9 g (24 mmol) of acetylchloride in 10 ml of methylene chloride was dropwise added with coolingwith ice. The mixture was stirred until the reaction mixture washomogeneous, and a solution of 4.5 g (20 mmol) of5-chloro-4,4,8-trimethylthiochroman in 10 ml of methylene chloride wasadded. The mixture was allowed to react at room temperature for 1 hour.After the completion of the reaction, the reaction mixture was pouredinto ice water and extracted with methylene chloride. An organic layerwas washed with a saturated sodium chloride aqueous solution and driedover anhydrous sodium sulfate. The methylene chloride was distilled offunder reduced pressure, and the resultant oily substance was purified bysilica gel column chromatography to give 3.0 g (yield 56%) of6-acetyl-5-chloro-4,4,8-trimethylthiochroman.

Step (2)

5 ml of acetic acid was added to 3.0 g (11 mmol) of6-acetyl-5-chloro-4,4,8-trimethylthiochroman, 3.7 g (33 mmol) of a 30%hydrogen peroxide aqueous solution was further added, and the mixturewas heated at 80° C. for 2 hours. 20 ml of a 2% sodium hydrogensulfitewas added to the reaction mixture, and a precipitated solid wasrecovered by filtration to give 2.8 g (yield 85%) of6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide.

N.M.R. (ppm, solvent: deuterochloroform, internal standard:tetramethylsilane): 1.67(6H,s), 2.30˜2.50(2H,m), 2.56(3H,s), 2.76(3H,s),3.30˜3.50(2H,m), 7.05(H,s)

Step (3)

3.6 Grams (85 mmol ) of sodium hydroxide was dissolved in 70 ml ofwater, and 1.5 ml (29 mmol) of bromine was added with cooling with ice.Further, 2.8 g (9.3 mmol) of6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide was added, andthe mixture was stirred for 3 hours and then heated at 100° C. for 5hours. After the completion of the reaction, ethyl acetate was added,and the mixture was liquid-separated. An aqueous layer was adjusted to apH of 1 by adding hydrochloric acid. The extraction of the aqueous layerwas carried out by adding ethyl acetate, and an organic layer was driedover anhydrous sodium sulfate. The ethyl acetate was distilled off underreduced pressure to give 2.1 g (yield 75%) of5-chloro-4,4,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deuteroacetone, internal standard:tetramethylsilane): 1.70(6H,s), 2.30˜2.50(2H,m), 2.75(3H,s),3.40˜3.60(2H,m), 7.50(H,s)

Intermediate Preparation Example 5

3,3,4,7-Tetramethyl-2-hydrobenzo[b]thiophene-5-carboxylicacid-1,1-dioxide used as a starting material in Preparation Example 43to be described later was prepared in the following steps. ##STR45##Step (1)

A 100-ml eggplant type flask was charged with 6.9 g (50 mmol) of2,5-dimethylthiophenol, 5.5 g (60 mmol, 1.2 equivalents) of methallylchloride which was a halogenated olefin, 6.9 g (50 mmol, 1 equivalent)of potassium carbonate and 30 ml of acetone, and the mixture wasrefluxed under heat for 1 hour. The reaction mixture was allowed tocool, insolubles were removed by filtration, and the acetone wasdistilled off. The resultant residue was re-dispersed in n-hexane andwashed with a saturated sodium chloride aqueous solution. An organiclayer was dried over anhydrous sodium sulfate, and then the solvent wasdistilled off to give 8.6 g (yield 89%) of2-methyl-3-(2,5-dimethylphenylthio)propane.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.87(3H,s), 2.28(3H,s), 2.33(3H,s), 3.49(2H,s),4.87(2H,m), 6.8-7.3(3H,m)

I.R. (KBr tablet, cm⁻¹): 3090, 2980, 1610

Step (2)

A 100-ml eggplant type flask was charged with 8.6 g (45 mmol) of the2-methyl-3-(2,5-dimethylphenylthio)-1-propane obtained in the above step(1)and 50 g of polyphosphoric acid (containing 300 mmol (6.7equivalents) of diphosphorus pentoxide (P₂ O₅)) as adehydration-condensation agent, and the mixture was allowed to react at150° C. for 2 hours. After the completion of the reaction, the reactionmixture was poured into ice water and extracted with n-hexane. Theresultant organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate. The solventwas distilled off to give a crude product, and the crude product waspurified by column chromatography (elution solvent: n-hexane) to give1.6 g (yield 19%) of 3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.45(6H,s), 2.21(3H,s), 2.36(3H,s), 3.08(2H,s),6.80(2H,dd)

I.R. (KBr tablet, cm⁻¹): 2970, 1465, 800

Step (3)

A 100-ml eggplant type flask was charged with 1.6 g (8 mmol) of the3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene obtained in the above step(2) and 30 ml of chloroform, and 0.55 ml (10.7 mmol, 1.34 equivalents)of bromine was dropwise added. The mixture was allowed to react at roomtemperature for 1 hour, and the reaction mixture was consecutivelywashed with a sodium hydrogensulfite and with a saturated sodiumchloride aqueous solution and dried over anhydrous sodium sulfate. Thesolvent was distilled off to give 1.9 g (yield 85%) of5-bromo-3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.48(6H,s), 2.18(3H,s), 2.41(3H,s), 3.08(2H,s),7.20(H,s)

I.R. (KBr tablet, cm⁻¹): 2950, 1440, 1100

Step (4)

A 100-ml three-necked flask was charged with 30 ml of THF and 0.7 g(24mmol, 3.4 equivalents) of magnesium, and 1.52 g (14mmol, 2equivalents) of ethyl bromide was dropwise added to activate themixture. Then, a solution of 1.9 g (7.0 mmol) of the5-bromo-3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene obtained in theabove step (3) in 5 ml of THF was dropwise added, and the mixture wasrefluxed under heat for 4 hours. The reaction mixture was allowed tocool to room temperature, and carbon dioxide gas was bubbled for 2hours. The reaction was terminated by adding 5% hydrochloric acid to thereaction mixture, and the reaction mixture was extracted with ethylacetate. The resultant organic layer was extracted with apotassiumcarbonate aqueous solution, and the resultant aqueous layer was washedwith ethyl acetate, then neutralized with 5% hydrochloric acid andextracted with ethyl acetate. The resultant organic layer was washedwith a saturated sodium chloride aqueous solution and then dried overanhydrous sodium sulfate, and the solvent was distilled off to give 1.2g (yield 70%) of3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene-5-carboxylic acid.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.51(6H,s), 2.22(3H,s), 2.58(3H,s), 3.12(2H,s),7.62(H,s)

I.R. (KBr tablet, cm⁻¹): 3500, 3000, 1690

Step (5)

A 100-ml eggplant type flask was charged with 1.2 g (4.9 mmol) of the3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene-5-carboxylic acid, 1.7 ml(15.0mmol, 3.1 equivalents) of 30% H₂ O₂ and 10 ml of acetic acid, andthe mixture was allowed to react at 100° C. for 2 hours. The reactionmixture was poured into a sodium hydrogensulfite and extracted withethyl acetate. The resultant organic layer was washed with a saturatedsodium chloride aqueous solution and dried over anhydrous sodiumsulfate, and the solvent was distilled off to give 1.0 g (yield 79%) of3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene-5-carboxylicacid-1,1-dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.69(6H,s), 2.63(6H,s), 3.38(2H,s), 7.30(H,s),7.72(H,s)

I.R. (KBr tablet, cm⁻¹): 3450, 1740

Intermediate Preparation Example 6

4,5,8-Trimethylthiochroman-6-carboxylic acid-1,1-dioxide used as astarting material in Preparation Example 44 to be described later wasprepared in the following steps. ##STR46## Step (1)

A 300-ml three-necked flask was charged with 55 ml (55 mmol, 3equivalents) of a 1M solution of magnesium methyl bromide (MeMgBr) and100 ml of tetrahydrofuran (THF), and the mixture was cooled with iceunder nitrogen current. To this mixture was dropwise added a solution of5.0 g (18.4 mmol) of 6-bromo-5,8-dimethylthiochroman-4-one in 15 ml ofTHF, and the mixture was stirred at room temperature for 3 hours andthen refluxed for 2 hours. To the reaction mixture was added 5% HCl, andthe mixture was extracted with ethyl acetate. The resultant organiclayer was washed with a saturated sodium chloride aqueous solution anddried over anhydrous sodium sulfate, and the solvent was distilled offto give 5.2 g (yield 99%) of 6-bromo-4,5,8-trimethylthiochroman-4-ol.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.60(3H,s), 2.20(3H,s), 2.26˜2.36(2H,m), 2.70(3H,s),2.80˜3.10(2H,m), 7.40(H,s)

Step (2)

A 200-ml flask equipped with a Dean Stark tube was charged with 5.4 g(18.8 mmol) of the 6-bromo-4,5,8-trimethylthiochroman-4-ol obtained inthe above step (1), 100 ml of benzene and 10 mg (0.06 mmol, 0.0032equivalent) of p-toluenesulfonic acid, and the mixture was refluxedunder heat for 1 hour. After cooled, the reaction mixture wasconsecutively washed with a sodium hydrogencarbonate aqueous solutionand with a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was distilled off, and theresultant residue (crude product) was purified by silica gel columnchromatography (developer solvent: hexane, ethyl acetate) to give 1.4 g(yield 27%) of 6-bromo-4,5,8-trimethyl-3,4-dehydrothiochroman.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 2.29(3H,s), 2.42(3H,s), 2.99(2H,dd), 6.02(H,t),7.22(H,s)

Step (3)

A 100-ml portable reactor was charged with 1.32 g of the6-bromo-4,5,8-trimethyl-3,4-dehydrothiochroman, 0.55 g of 5% Pd/C and 20ml of chloroform, and the mixture was allowed to react under a hydrogenpressure of 5 kg/cm² G at room temperature for 6 hours. After thecompletion of the reaction, the catalyst was separated by filtration,and the solvent was distilled off to give 1.21 g (yield 91%) of6-bromo-4,5,8-trimethylthiochroman.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.15(3H,d), 2.20(3H,s), 2.38(3H,s), 1.8˜2.3(H,m),2.9˜3.1(2H,m), 3,2˜3.4(2H,m), 7.20(H,s)

Step (4)

A 50-ml three-necked flask was charged with 15 ml of THF and 0.43 g (18mmol) of magnesium, and 0.97 g (9 mmol) of ethyl bromide was dropwiseadded to activate the mixture. Then, a solution of 1.21 g (4.5 mmol) ofthe 6-bromo-4,5,8-trimethylthiochroman in 3 ml of THF was dropwiseadded, and the mixture was refluxed under heat for 6 hours. The reactionmixture was allowed to cool to room temperature, and CO₂ gas wasbubbled. The reaction was terminated by adding 5% hydrochloric acid, andthe reaction mixture was extracted with ethyl acetate. An organic layerwas extracted with a potassium carbonate aqueous solution, and anaqueous layer was washed with ethyl acetate and neutralized with 5%hydrochloric acid. The so-formed carboxylic acid was extracted withethyl acetate, washed with a saturated sodium chloride aqueous solutionand then dried over sodium sulfate. The solvent was distilled off togive 0.75 g (yield 71%) of 4,5,8-trimethylthiochroman-6-carboxylic acid.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.14(3H,d), 2.23(3H,s), 1.75˜2.35(2H,m), 2.55(3H,s),2.9˜3.1(2H,m), 3.2˜3.5 (2H,m), 7.60(H,s)

Step (5)

A 30-ml eggplant type flask was charged with 0.75 g (3.2 mmol) of the4,5,8-trimethylthiochroman-6-carboxylic acid, 1.1 g (9.5 mmol) of 30%hydrogen peroxide and 1 ml of acetic acid, and the mixture was allowedto react at 100° C. for 2 hours. The reaction mixture was poured into asodium hydrogensulfite aqueous solution and extracted with ethylacetate. The extract was washed with a saturated sodium chloride aqueoussolution and dried over sodium sulfate, and the solvent was distilledoff to give 0.76 g (yield 98%) of4,5,8-trimethylthiochroman-6-carboxylic acid-1,1,dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.35(3H,d), 2.0˜2.4(H,m), 2.57(3H,s), 2.77(3H,s),3.3˜3.8 (4H,m), 7.67(H,s)

Intermediate Preparation Example 7

4-Ethyl-5,8-dimethylthiochroman-6-carboxylic acid-1,1,dioxide used as astarting material in Preparation Example 45 to be described later wasprepared in the following steps. ##STR47## Step (1)

0.5 ml of triethylamine was added to a mixture containing 10.0 g(72.5mmol) of 2,5-dimethylthiophenol, 7.32 g (87.0 mmol)of ethyl vinylketone and 30 ml of dichloroethane, and the mixture was stirred for 1hour. The mixture was diluted with dichloromethane, washed with asaturated sodium hydrogencarbonate aqueous solution, dried overanhydrous sodium sulfate and filtered, and the solvent was removed underreduced pressure to give 16.1 g (yield 100%) of(2,5-dimethylphenyl)-3-oxopentylsulfide in the form of a colorlesstransparent oil.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.05(3H,t,J=7Hz), 2.31(6H,s), 2.43(2H,q,J=7 Hz),2.6˜2.9(2H,m), 3.0˜3.3 (2H,m), 6.9˜7.2(3H,m)

Step(2)

1.65 g (43.6 mmol) of sodium borohydride was gradually added to 16.1 g(72.6 mmol) of the (2,5-dimethylphenyl)-3-oxopentylsulfide and 64 ml ofethanol at 0° C., and the mixture was stirred at room temperature for 1hour. The mixture was poured into ice and an aqueous solution containing5% hydrochloric acid and extracted with dichloroethane. The extract wasdried over anhydrous sodium sulfate and filtered, and the solvent wasdistilled off under reduced pressure to give 16.3 g of(2,5-dimethylphenyl)-3-hydroxypentylsulfide in the form of a colorlesstransparent oil.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 0.59(3H,t), 1.3˜1.9(4H,m), 2.31(6H,s),2.9˜3.1(2H,m), 3.6˜3.9 (H,m), 6.8˜7.2(3H,m)

Step (3)

4.94 ml (67.8 mmol) of thionyl chloride was gradually dropwise added toa mixture containing 10.0 g (45.2 mmol) of the(2,5-dimethylphenyl)-3-hydroxypentylsulfide and 30 ml of dichloroethane,and the mixture was stirred at 60° C. for 2 hours. The reaction mixturewas cooled to room temperature, and the solvent was distilled off underreduced pressure. Dichloromethane was added to the resultant residue,the mixture was washed with a saturated sodium hydrogencarbonate aqueoussolution and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to give 10.9 g (yield 99%) of(2,5-dimethylphenyl)-3-chloropentylsulfide as a crude product. Thiscompound was used for a subsequent reaction without purifying it anyfurther.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.03(3H,t), 1.5˜2.4 (4H,m), 2.32(6H,s),2.8˜3.2(2H,m), 3.9˜4.2 (H,m), 6.8˜7.2(3H,m)

Step (4)

A mixture of 9.40 g (38.7 mmol) of the(2,5-dimethylphenyl)-3-chloropentylsulfide with dichloromethane wasgradually dropwise added to a suspension containing 5.18 g (38.7 mmol)of aluminum chloride and 20 ml of methylene chloride at 0° C., and theresultant mixture was stirred at 0° C. for 2 hours and further stirredat room temperature for 2 hours. The reaction mixture was poured intoice water and extracted with methylene chloride. The extract was driedover anhydrous sodium sulfate and filtered, and the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography (silica gel; hexane→hexane/ethyl acetate=20:1) to give3.64 g (yield 47%) of 4-ethyl-5,8-dimethylthiochroman in the form of abrown oil.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 0.9˜1.1(3H,m), 1.4˜2.5 (10H,m), 2.8˜4.1(3H,m),6.8˜7.2 (2H,m)

Step (5)

A mixed solution containing 1.91 g (9.26 mmol) of the4-ethyl-5,8-dimethylthiochroman and dichloromethane was dropwise addedto a mixed solution containing 1.49 g (11.1 mmol) of aluminum chloride,0.82 ml (11.6 mmol) of acetyl chloride and 6 ml of dichloromethane at 0°C., and the mixture was stirred for 1.5 hours. The reaction mixture waspoured into ice and a solution containing 5% hydrochloric acid andextracted with dichloromethane. The extract was washed with a saturatedsodium hydrogencarbonate, dried over anhydrous sodium sulfate andfiltered, and the solvent was distilled off under reduced pressure togive 1.66 g (yield 72%) of 6-acetyl-4-ethyl-5,8-dimethylthiochroman.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 0.99(3H,t), 1.3˜1.8(2H,m), 2.2˜2.6(2H,m),2.25(3H,m), 2.38(3H,s), 2.53(3H,s), 2.8˜3.8 (3H,m), 7.21(H,s)

Step (6)

A mixed solution containing 1.66 g (6.68 mmol) of the6-acetyl-4-ethyl-5,8-dimethylthiochroman, 2.28 g (20.1 mmol) of a 30%hydrogen peroxide aqueous solution and 2.0 ml of acetic acid was allowedto react at 80° C. for 2 hours. The reaction mixture was cooled to roomtemperature, a 2% sodium hydrogensulfite aqueous solution was added, andthe mixture was extracted with ethyl acetate and washed with a saturatedsodium hydrogencarbonate and then with a saturated sodium chlorideaqueous solution. An organic layer was dried over anhydrous sodiumsulfate and filtered, and then the solvent was distilled off underreduced pressure. The residue was purified by column chromatography(silica gel; hexane/ethyl acetate=2:1) to give 1.03 g (yield 55%) of6-acetyl-4-ethyl-5,8-dimethylthiochroman-1,1-dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.53(3H,t,J=7 Hz), 1.42(2H,m), 2.2˜2.6 (2H,m),2.31(3H,s), 2.53(3H,s), 2.75(3H,s), 2.9˜3.8(3H,s), 7.20(H,s)

Step (7)

13 ml of a sodium hypochlorite aqueous solution was dropwise added to amixed solution containing 1.03 g (3.67 mmol) of the6-acetyl-4-ethyl-5,8-dimethylthiochroman-1,1-dioxide and 4 ml of dioxaneat 0° C., and the mixture was stirred at 0° C. for 1 hour. Further, themixture was stirred at room temperature overnight. 5 ml of a 20% sodiumsulfite aqueous solution was added to the mixture, and the mixture waswashed with dichloromethane. An aqueous layer was acidified (pH 1) withconcentrated hydrochloric acid, extracted with ethyl acetate, dried overanhydrous sodium sulfate and filtered, and the solvent was distilled offunder reduced pressure to give 0.90 g (yield 87%) of4-ethyl-5,8-dimethylthiochroman-1,1-dioxide-6-carboxylic acid.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 1.07(3H,t), 1.5˜1.8 (2H,m), 2.3˜2.7 (2H,m),2.49(3H,s), 2.69(3H,s), 3.0˜3.9 (3H,m), 7.55(H,s)

Intermediate Preparation Example 8

3,4,7-Trimethyl-2-hydrobenzo[b]thiophene-5-carboxylic acid-1,1-dioxideused as a starting material in Preparation Example 46 to be describedlater was prepared in the following steps. ##STR48## Step (1)

A 100-ml eggplant type flask was charged with 4.0 g (29 mmol) of2,5-dimethylthiophenol as a substituted thiophenol, 3.2 g (35mmol, 1.2equivalents) of chloroacetone as an α-halo-carbonyl compound, 4.0 g(29mmol, 1 equivalent) of anhydrous potassium carbonate and 30 ml ofacetone, and the mixture was refluxed under heat for 2 hours. Thereaction mixture was allowed to cool, then, insolubles were removed byfiltration, and the acetone was distilled off. The resultant residue wasre-dispersed in n-hexane and washed with a saturated sodium chlorideaqueous solution. An organic layer was dried over anhydrous sodiumsulfate, and then the solvent was distilled off. To the resultantresidue was added 100 g of polyphosphoric acid as adehydration-condensation agent, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into ice water,and a white crystal which precipitated was re-dispersed in n-hexane andwashed with a saturated sodium chloride aqueous solution. The solventwas distilled off to give 4.5 g (yield 88%) of 3,4,7-trimethylthiophene.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 2.48(3H,s), 2.62(3H,s), 2.72(3H,s), 2.98(3H,s)

Step (2)

A 50-ml eggplant type flask was charged with 1.0 g of the3,4,7-trimethylbenzo[b]thiophene obtained in the above step (1), 30 mlof ethanol and 50 mg of platinum oxide, to carry out hydrogenation underatmospheric pressure. After the completion of the reaction, the ethanolwas distilled off to give 0.94 g (yield 93%) of3,4,7-trimethyl-2-hydrobenzo[b]thiophene.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.24(3H,d), 2.21(3H,s), 2.26(3H,s), 2.7˜3.1(H,m),3.4-3.8(2H,m), 6.98(3H,s)

Step (3)

A 100-ml eggplant type flask was charged with 2.33 g (16.0mmol, 1.2equivalents) of aluminum chloride and 10 ml of dichloromethane, and themixture was cooled with ice. To the mixture was dropwise added 1.15 ml(1.26 g, 17.5 mmol, 1.1 equivalents) of acetyl chloride, and the mixturewas stirred under cooling with ice for 15 minutes. Then, a solution of2.60 g (14.6 mmol) of 3,4,7-trimethyl-2-hydrobenzo[b]thiophene in 10 mlof dichloromethane was dropwise added.

The mixture was stirred with cooling with ice for 30 minutes, stirred atroom temperature for 3 hours, and poured into ice water to terminate thereaction. An aqueous layer was extracted with dichloromethane, and anorganic layer was washed with a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 2.48 g (yield 77%) of5-acetyl-3,4,7-trimethyl-2-hydrobenzo[b]thiophene.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.24(3H,d), 2.25(3H,s), 2.43(3H,s), 2.54(3H,s),2.95(H,d), 3.5˜3.8(2H,m), 7.30(H,s)

Step (4)

A 30-ml eggplant type flask was charged with 2.48 g (11.3 mmol) of the5-acetyl-3,4,7-trimethyl-2-hydrobenzo[b]thiophene, 3.8 ml of a 30%hydrogen peroxide aqueous solution and 3 ml of acetic acid, and themixture was allowed to react at 100° C. for 2 hours. The reactionmixture was poured into a sodium sulfite aqueous solution and extractedwith ethyl acetate. The extract was washed with a saturated sodiumchloride aqueous solution and dried over sodium sulfate, and then thesolvent was distilled off to give 2.67 g (yield 94%) of5-acetyl-3,4,7-trimethyl-2-hydrobenzo[b]thiophene-1,1-dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.50(3H,d), 2.39(3H,s), 2.57(3H,s), 2.63(3H,s),3.25(H,d), 3.5˜3.75(2H,m), 7.35(H,s)

Step (5)

A 50-ml eggplant type flask was charged with 11.6 ml of 6.3%hypochlorous acid and the content was cooled with ice. A solution of2.67 g (10.6 mmol) of5-acetyl-3,4,7-trimethyl-2-hydrobenzo[b]thiophene-1,1-dioxide in 10 mlof 1,4-dioxane was dropwise added. After the addition, the mixture wastemperature-increased up to room temperature and then stirred for 3hours. Then, a sodium sulfite aqueous solution was added, the reactionmixture was washed with methylene chloride twice, and then 10 ml ofconcentrated hydrochloric acid was added with cooling with ice. Themixture was extracted with ethyl acetate three times, and then driedover anhydrous sodium sulfate. The solvent was distilled off to give2.38 g (yield 88%) of3,4,7-trimethyl-2-hydrobenzo[b]thiophene-5-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.50(3H,d), 2.58(3H,s), 2.65(3H,s), 3.28(H,d),3.5˜3.75(2H,m), 7.85(H,s)

Intermediate Preparation Example 9

5,8-Dimethyl-3,4-dehydrothiochroman-6-carboxylic acid used as a startingmaterial in Preparation Example 47 to be described later was prepared inthe following steps. ##STR49## Step (1)

In a 100-ml eggplant type flask, 5.0 g (18.4 mmol) of6-bromo-5,8-dimethylthiochroman-4-one as a halogenated thiochroman-4-onecompound was dissolved in 30 ml of methanol, and 0.35 g (9.2 mmol, 0.5equivalent) of sodium borohydride as a reducing agent was added at roomtemperature. The reaction mixture was stirred for 2 hours, then, dilutedhydrochloric acid was added, and the mixture was extracted with ethylacetate. An organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate, and thensolvent was distilled off to give 0.49 g (yield 95%) of6-bromo-5,8-dimethylthiochroman-4-ol.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.8˜3.3(4H,m), 2.21(3H,s), 2.42(3H,s), 5.06(H,t),7.30(H,s)

Step (2)

A 200-ml flask equipped with a Dean Stark tube was charged with 4.0 g(16.6 mmol) of the 6-bromo-5,8-trimethylthiochroman-4-ol obtained in theabove step (1), 100 ml of benzene and 10 mg (0.06 mmol, 0.0036equivalent) of p-toluenesulfonic acid, and the mixture was refluxedunder heat for 1 hour. After cooled, the reaction mixture wasconsecutively washed with a sodium hydrogencarbonate aqueous solutionand with a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was distilled off to give 2.6 g(yield 69%) of 6-bromo-5,8-dimethyl-3,4-dehydrothiochroman.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 2.30(6H,s), 3.32(2H,dd), 5.9˜6.2(H,m), 6.6˜7.0(2H,m)

Step (3)

A 200-ml three necked flask was charged with 50 ml of THF and 0.56 g (23mmol, 1.2 equivalents) of magnesium, and the mixture was activated byadding 1 pieces of iodine and 5 drops of ethyl Bromide. Then, a solutionof 4.88 g (19 mmol) the 6-bromo-5,8-dimethyl-3,4-dehydrothiochromanobtained in the above step (2) in 5 ml of THF was dropwise added, andthe mixture was refluxed under heat for 4 hours. The reaction mixturewas allowed to cool to room temperature, and then carbon dioxide gas wasbubbled for 2 hours. The reaction was terminated by dropwise adding 5%hydrochloric acid, and the reaction mixture was extracted with ethylacetate. The resultant organic layer was extracted with a potassiumcarbonate aqueous solution, an aqueous layer was washed with ethylacetate, neutralized by adding 5% hydrochloric acid and extracted withethyl acetate. The resultant organic layer was washed with a saturatedsodium chloride aqueous solution and dried over anhydrous sodiumsulfate, and the solvent was distilled off to give 1.9 g (yield 46%) of5,8-dimethyl-3,4-dehydrothiochroman-6-carboxylic acid.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 2.32(3H,s), 2.60(3H,s), 3.33(2H,dd), 5.9˜6.1(H,m),6.81(H,d), 7.67(H,s)

I.R. (KBr tablet, cm⁻¹): 3300˜2600, 1680

Intermediate Preparation Example 10

5-Methyl-3,4-dehydrothiochroman-6-carboxylic acid-1,1,dioxide used as astarting material in Preparation Example 48 to be described later wasprepared in the following steps. ##STR50## Step (1)

80 ml (100 g, 621 mmol) of 3,4-dichlorotoluene as a halogen-substitutedbenzene derivative was added to a solution of 100 g (750 mmol, 1.21equivalents) of aluminum chloride as an acid catalyst in 250 ml of1,2-dichloroethane, and then 55 ml (774 mmol, 1.25 equivalents) ofacetyl chloride as an acetylating agent was dropwise added at roomtemperature. After the completion of the addition, the reaction mixturewas stirred at room temperature for 10 minutes and then stirred at70°˜75° C. for 5 hours. After cooled, the reaction mixture was graduallyadded to 300 ml of ice water and separated to two layers. The resultantorganic layer was concentrated. The resultant aqueous layer wasextracted with ethyl acetate to obtain an organic layer, and the organiclayer was added to the above-concentrated organic layer. The organiclayer mixture was washed with 5% hydrochloric acid once, with a sodiumcarbonate aqueous solution twice and with a saturated sodium chlorideaqueous solution once, and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to give 125.1 g (yield86%) of 3,4-dichloro-6-methylacetophenone as a crude product.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 2.47(3H,s), 2.58(3H,s), 7.50(H,s), 7.97(H,s)

Step (2.)

1,350 ml (1.96 mol, 3 equivalents) of a 12.9% sodium hypochlorite as anoxidizing agent was diluted with 400 ml of water, and cooled to 8° C.with cooling with ice. To this mixture was dropwise added a solution of132.3 g (652 mmol) of the 3,4-dichloro-6-methylacetophenone obtained inthe above step (1) in 130 ml of dioxane at 10° C. or lower, and further,130 ml of dioxane was added. Then, the ice bath was removed, and themixture was stirred at room temperature. After the temperature insidethe reaction system reached 15° C., the reaction mixture was againstirred with cooling with ice for 1 hour. Further, the ice bath wasremoved, and the reaction mixture was stirred at room temperature for3.0 hours. Then, 50 ml of an aqueous solution containing 10.0 g (79mmol) of sodium sulfite was added. The reaction mixture was washed withmethylene chloride twice, and then 170 ml of concentrated hydrochloricacid was added with cooling with ice. The mixture was extracted withethyl acetate 3 times, and then the resultant organic layer was driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to give 119.3 g (yield 83%) of3,4-dichloro-6-methylbenzoic acid as a crude product.

N.M.R. (ppm, solvent: acetone d-6, internal standard:tetramethylsilane): 2.59(3H,s), 7.52(H,s), 8.04(H,s)

Step (3)

9.2.1 g (421 mmol) of the 3,4-dichloro-6-methylbenzoic acid obtained inthe above step (2) was dissolved in 550 ml of ethanol as both anesterifying agent and a solvent, 20 ml of concentrated sulfuric acid asan acid catalyst was added, and the mixture was refluxed under heat for7 hours. The ethanol was distilled off under reduced pressure, ice waterwas added, and the mixture was extracted with ethyl acetate twice. Theresultant organic layer was consecutively washed with a sodium carbonateaqueous solution and with a saturated sodium chloride aqueous solutionand dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to give 103.4 g (yield 97%) of ethyl3,4-dichloro-6-methylbenzoate as a crude product.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 1.39(3H,t), 2.57(3H,s), 4.35(2H,s), 7.52(H,s),7.98(H,s)

Step (4)

23.4 ml (268 mmol, 1.1 equivalents) of 3-mercaptopropionic acid wasadded to 215 ml of a solution of 53.7 g (231 mmol) of the ethyl3,4-dichloro-6-methylbenzoate obtained in the step (3) and 37.9 g (268mmol, 1.1 equivalents) of potassium carbonate in N,N-dimethylformamide(DMF) at room temperature, and then the mixture was stirred under heatat 120°˜125° C. for 2 hours and 20 minutes. The reaction mixture wascooled to about 50° C., ethyl acetate and water were added, and forremoving the DMF and neutral components, the reaction mixture was washedwith ethyl acetate four times and with hexane once. Concentratedhydrochloric acid was added to the resultant aqueous layer toprecipitate a crystal, the mixture was allowed to stand for a while, andthe crystal was recovered by filtration and washed with water threetimes. The so-obtained crystal was dissolved in ethyl acetate, theobtained organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure to give 50.4 g (yield 60%) of3-(2-chloro-4-ethoxycarbonyl-5-methylphenylthio)propionic acid as acrude product.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 1.38(3H,t), 2.58(3H,s), 2.79(2H,t), 3.35 (2H,t),7.33(H,s), 7.87(H,s)

Step (5)

167 g of polyphosphoric acid as an acid catalyst was heated to 80°˜85°C., and 47.7 g (157 mmol) of the3-(2-chloro-4-ethoxycarbonyl-5-methylphenylthio)propionic acid obtainedin the above step (4) was added thereto over 5 minutes. Then, themixture was stirred under heat for 1 hour and 20 minutes. The reactionmixture was allowed to cool to room temperature and then added slowly toa mixture containing 191 g (1.80 mol) of sodium carbonate and ice, andthe mixture was stirred at room temperature until the sodium carbonatewas nearly dissolved. The reaction mixture was extracted with ethylacetate twice, and the resultant organic layer was washed with a sodiumcarbonate aqueous solution twice, with water twice and with a saturatedsodium chloride aqueous solution one time, and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure togive 41.3 g (yield 5%) of8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one as a crude product.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 1.38(3H,t), 2.58(3H,s), 2.9˜3.1(2H,m),3.3˜3.5(2H,m), 4.34(2H,q), 7.81(H,s)

Step (6)

88.4 g (311 mmol) of the8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one obtained in theabove step (5) was dissolved in 200 ml of ethanol, and further dissolvedin 200 ml of dichloromethane. This solution was cooled to 5°˜10° C., and5.9 g (155 mmol) of sodium borohydride was added. The reaction mixturewas stirred at the above temperature for 30 minutes, and further stirredat room temperature for 3 hours. Then, the reaction mixture was pouredinto 400 ml of a 5% hydrochloric acid aqueous solution and extractedwith 900 ml of dichloromethane, and then the resultant organic layer waswashed with a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was distilled off to give 86.8 g(yield 97%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-ol.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 1.35(3H,t), 1.6˜3.7 (5H,m), 2.62(3H,s),4.1˜4.8(H,bs), 4.32(2H,q), 5.13(H,m), 7.71(H,s)

Step (7)

25.8 g (90.0 mmol) of the8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-ol obtained in the abovestep (6) was dissolved in 70 ml of acetic acid, 46.0 ml (0.45 mol, 5.0equivalents) of a 30% hydrogen peroxide aqueous solution was added, andthe mixture was stirred under heat at 80° C. for 4 hours. The reactionmixture was allowed to cool, and the resultant solid was recovered byfiltration, washed with 200 ml of water and dried under reduced pressureto give 21.9 g (yield 95%) of8-chloro-6-ethoxycarbonyl-4-hydroxy-5-methylthiochroman-1,1-dioxide.

N.M.R. (ppm, solvent: deutero chloroform, internal standard:tetramethylsilane): 1.40(3H,t), 2.59(3H,s), 2.5˜4.2(4H,m), 4.40(2H,q),5.09(H,bs), 7.67(H,s)

Step (8)

10.0 g (31.3 mmol) of the8-chloro-6-ethoxycarbonyl-4-hydroxy-5-methylthiochroman-1,1-dioxideobtained in the above step (7) was dissolved in 30 ml of ethanol, and 50ml of a 16% potassium hydroxide aqueous solution and 6.1 g (93.3 mmol,3.0 equivalents) of a zinc powder were added. The mixture was stirredunder heat at 50° C. for 3 hours. After the completion of the reaction,the zinc powder was filtered off. While the reaction mixture was cooled,a 2N hydrochloric acid aqueous solution was added until the mixture hada pH of 1. Then, the mixture was extracted with ethyl acetate twice. Anorganic layer was washed with a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate, and the solventwas distilled off to give 11.5 g (yield 100%) of4-hydroxy-5-methylthiochroman-6-carboxylic acid-1,1dioxide.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 2.5˜2.8(2H,m), 2.69(3H,s), 3.1˜4.1(2H,m), 5.22(H,t),7.75(H,d), 7.94(H,d)

m.p. 172°18 173° C.

Step (9)

3.0 g (11.8 mmol) of the 4-hydroxy-5-methylthiochroman-6-carboxylicacid-1,1-dioxide obtained in the above step (8) was dissolved in 10 mlof toluene, 0.1 ml of concentrated sulfuric acid was added, and themixture was stirred under heat at 70° C. for 5 hours. After thecompletion of the reaction, while the reaction mixture was cooled, asaturated sodium hydrogencarbonate aqueous solution was added until themixture had a pH of 10. Then, impurities were extracted with ethylacetate. Then while an aqueous layer was in ice bath, 5% hydrochloricacid was added to the aqueous layer until it had a pH of 1. The mixturewas extracted with ethyl acetate twice. An organic layer was washed witha saturated sodium chloride aqueous solution and dried over anhydroussodium sulfate, and the solvent was distilled off to give 2.5 g (yield89%) of 5-methyl-3,4-dehydrothiochroman-6-carboxylic acid-1,1-dioxide.

N.M.R. (ppm, solvent: deutero acetone, internal standard:tetramethylsilane): 2.62(3H,s), 4.10(2H,m), 6.45(H,ddd), 7.20(H,d),7.83(H,d), 7.95(H,d) mp.183°˜186° C.

Preparation Examples of the novel pyrazole derivative for achieving thefirst object of the present invention will be explained hereinafter.

Preparation Example 1

7.4 Grams (0.026 mol) of the 4,4,5,8-tetramethylthiochroman-6-carboxylicacid-1,1-dioxide obtained in Intermediate Preparation Example 1, 3.4 g(0.03 mol) of 1-ethyl-5-hydroxypyrazole and 6.22 g (0.03 mol) of DCC(N,N'-dicyclohexylcarbodiimide) were added to 50 ml of tert-amyl alcoholall at once, and the mixture was stirred at room temperature for 30minutes. Then, 1.8 g (0.013 mol) of anhydrous potassium carbonate wasadded. The reaction mixture was allowed to react at 80° C. for 8 hours,then, the reaction solvent was distilled off under reduced pressure, andthe resultant residue was separated into two layers by dispersing it ina 5% potassium carbonate aqueous solution and ethyl acetate. Further, anaqueous layer was adjusted to a pH of 1 with 5% hydrochloric acid, and aformed solid was recovered by filtration to give 6.13 g (yield 62%) of4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.

Preparation Examples 2-5

Compounds shown in the right column of Table 1 were obtained in the samemanner as in Preparation Example 1 except that raw materials shown inthe left column of Table 1 were used in place of the4,4,5,8-tetramethylthiochroman-6-carboxylic acid-1,1-dioxide inPreparation Example 1.

Preparation Example 6

4,4,5,8-Tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxidein an amount of 0.46 g (yield 70%) was obtained in the same manner as inPreparation Example 1 except that 1,3-dimethyl-5-hydroxypyrazole wasused in place of the 1-ethyl-5-hydroxypyrazole in Preparation Example 1.

Table 1 shows the raw materials used in Preparation Examples 1 to 6 andthe structural formulae and yields of the compounds obtained inPreparation Examples 1 to 6. Table 2 shows the physical properties ofthe compounds.

                                      TABLE 1                                     __________________________________________________________________________    Pre.               Comp.                                                                             Structural          Yield                              Ex.                                                                              Raw material    No. formula             (%)                                __________________________________________________________________________        ##STR51##      1                                                                                  ##STR52##          62                                 2                                                                                 ##STR53##      2                                                                                  ##STR54##          46                                 3                                                                                 ##STR55##      3                                                                                  ##STR56##          48                                 4                                                                                 ##STR57##      4                                                                                  ##STR58##          64                                 5                                                                                 ##STR59##      5                                                                                  ##STR60##          72                                 6                                                                                 ##STR61##      6                                                                                  ##STR62##          70                                 __________________________________________________________________________     Pre. Ex. = Preparation Example                                           

                                      TABLE 2                                     __________________________________________________________________________                   N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane        I.R. (cm.sup.-1)                                          Solvent: deutero    KBr tablet                                                                            Melting point                      Pre. Ex.                                                                            Compound No.                                                                           chloroform          method  (°C.)                       __________________________________________________________________________    1     1        1.45(3H, t)1.55(6H, s)2.30-2.50(2H, m)                                                            2550-3500,                                                                            208.8-209.3                                       2.50(3H, s)2.80(3H, s)3.40-3.60(2H, m)                                                            2950, 3000,                                               4.10(2H, q)6.20(H, s)7.20(H, s)                                                                   1630, 1290,                                                                   1130                                       2     2        1.38(3H, t)1.60(6H, s)2.38-2.55(2H, m)                                                            2550-3500,                                                                            glass-like substance                              2.70(3H, s)3.40-3.54(2H, m)4.00(2H, q)                                                            2950, 3000,                                               7.30(H, s)7.45(H, d)7.80(H, d)*                                                                   1620, 1290,                                                                   1130                                       3     3        1.48(3H, t)1.70(6H, s)2.20-2.42(2H, m)                                                            2500-3500,                                                                            263.7-263.9                                       3.40-3.60(2H, m)4.08(2H, q)7.25(H, s)                                                             2950, 3000,                                               7.42(H, s)          1660, 1320,                                                                   1160                                       4     4        1.38(6H, s)1.46(3H, t)1.90-2.10(2H, m)                                                            not measured                                                                          glass-like substance                              3.00-3.20(2H, m)4.10(2H, q)7.20(H, d)                                         7.60(H, dd)7.76(H, s)7.95(H, d)                                5     5        1.40(3H, t)1.46(6H, s)2.35-2.50(2H, m)                                                            not measured                                                                          glass-like substance                              3.45-3.60(2H, m)4.05(2H, q)7.68(H, s)                                         7.86-8.06(3H, m)**                                             6     6        1.55(6H, s)1.65(3H, s)2.30-2.50(2H, m)                                                            2570-3700,                                                                            glass-like substance                              2.45(3H, s)2.80(3H, s)3.30-3.50(2H, m)                                                            2950, 1630,                                               3.65(3H, s)7.00(H, s)                                                                             1290, 1130                                 __________________________________________________________________________     *Solvent: deuteroacetone                                                      **Solvent: deuteromethanol                                               

Preparation Example 7

0.70 Grams (1.9 mmol) of the of the4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 1 was dissolved in 8 ml of methylenechloride. Then, 0.51 g (3.8 mmol) of potassium carbonate was dissolvedin 5 ml of water, and the resultant solution was added. Further, 0.43 g(3.8 mmol) of methanesulfonyl chloride and 0.05 g (0.2 mmol) ofbenzyltriethylammonium chloride were added. The mixture was allowed toreact at room temperature for 2 hours, and then further refluxed underheat for 2 hours. The reaction mixture was allowed to cool, and then amethylene chloride layer was collected and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresultant oil was purified by silica gel column chromatography to give0.41 g (yield 49%) of4,4,5,8-tetramethyl-6-(1-ethyl-5-methanesulfonyloxypyrazol-4-yl)carbonylthiochroman -1,1-dioxide (Compound 7).

Preparation Examples 8-17

Compounds 8 to 17 shown in the right column of Table 3 were obtained inthe same manner as in Preparation Example 7 except that reactionreagents shown in the left column of Table 3 were used in place ofmethanesulfonyl chloride used in Preparation Example 8.

Preparation Example 18

0.5 Grams (1.3 mmol) of the of the4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 1 was dissolved in 10 ml of methylenechloride, and 0.27 g (2.6 mmol) of triethylamine and 0.21 g (2.6 mmol)of acetyl chloride were added. The mixture was allowed to react at roomtemperature for 8 hours. Water was added to the reaction mixture toseparate a methylene chloride layer, and the methylene chloride layerwas dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the resultant oil was purified by silica gelcolumn chromatography to give 0.32 g (yield 58%) of4,4,5,8-tetramethyl-6-(1-ethyl-5-acetoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 18).

Preparation Examples 19-23

Compounds 19 to 23 shown in the right column of Table 3 were obtained inthe same manner as in Preparation Example 18 except that reactionreagents shown in the left column of Table 3 were used in place of theacetyl chloride used in Preparation Example 18.

Preparation Example 24

0.5 Grams (1.3 mmol) of the of the4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 1 was dissolved in 10 ml of methyl ethylketone, and 0.14 g (1.4 mmol) of chloroacetone and 0.37 g (2.6 mmol) ofpotassium carbonate were added. The mixture was refluxed under heat for4 hours. The solvent was distilled off under reduced pressure, ethylacetate was added to the resultant residue, and the mixture was washedwith a saturated sodium bicarbonate aqueous solution. An organic layerwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The resultant oil was purified by silica gelcolumn chromatography to give 0.42 g (yield 73%) of Compound 24.

Preparation Example 25

Compound 25 in an amount of 0.61 g (yield 92%) was obtained in the samemanner as in Preparation Example 24 except that phenacyl bromide wasused in place of the chloroacetone used in Preparation Example 24.

Table 3 shows the structural formulae and yields of Compounds obtainedin Preparation Examples 7 to 25. Table 4 shows the physical propertiesof the Compounds.

                                      TABLE 3                                     __________________________________________________________________________    Pre.                                                                             reaction      Comp.                                                                             Structural            Yield                              Ex.                                                                              reagent       No. formula               (%)                                __________________________________________________________________________    7  ClSO.sub.2 CH.sub.3                                                                         7                                                                                  ##STR63##            49                                 8  ClSO.sub.2 C.sub.2 H.sub.5                                                                  8                                                                                  ##STR64##            82                                 9  ClSO.sub.2 -n-C.sub.3 H.sub.7                                                               9                                                                                  ##STR65##            41                                 10 ClSO.sub.2 -n-C.sub.4 H.sub.9                                                               10                                                                                 ##STR66##            65                                 11 ClSO.sub.2 -n-C.sub.8 H.sub.17                                                              11                                                                                 ##STR67##            49                                 12                                                                                ##STR68##    12                                                                                 ##STR69##            60                                 13                                                                                ##STR70##    13                                                                                 ##STR71##            62                                 14                                                                                ##STR72##    14                                                                                 ##STR73##            73                                 15                                                                                ##STR74##    15                                                                                 ##STR75##            77                                 16                                                                                ##STR76##    16                                                                                 ##STR77##            72                                 17                                                                                ##STR78##    17                                                                                 ##STR79##            72                                 18                                                                                ##STR80##    18                                                                                 ##STR81##            58                                 19                                                                                ##STR82##    19                                                                                 ##STR83##            61                                 20                                                                                ##STR84##    20                                                                                 ##STR85##            54                                 21                                                                                ##STR86##    21                                                                                 ##STR87##            86                                 22                                                                                ##STR88##    22                                                                                 ##STR89##            74                                 23                                                                                ##STR90##    23                                                                                 ##STR91##            67                                 24                                                                                ##STR92##    24                                                                                 ##STR93##            73                                 25                                                                                ##STR94##    25                                                                                 ##STR95##            92                                 __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________                 N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane        I.R. (cm.sup.-1)                                          Solvent: deutero    KBr tablet                                                                           Melting point                         Pre. Ex.                                                                            Comp. No.                                                                            chloroform          method (°C.)                          __________________________________________________________________________    7     7      1.55(3H, t)1.60(6H, s)2.30-2.60(2H, m)                                                            2980, 1665,                                                                          202.2-203.4                                        2.50(3H, s)2.80(3H, s)3.30-3.60(2H, m)                                                            1140, 1300,                                               3.65(3H, s)4.25(2H, q)7.10(H, s)                                                                  1200, 1390                                                7.40(H, s)                                                       8     8      1.50(3H, t)1.60(6H, s)1.70(3H, t)                                                                 2940, 3000,                                                                          164.1-165.7                                        2.30-2.60(2H, m)2.50(3H, s)2.80(3H, s)                                                            1660, 1180,                                               3.30-3.60(2H, m)3.80(2H, q)4.20(2H, q)                                                            1140, 1290,                                               7.10(H, s)7.40(H, s)                                                                              1380                                         9     9      1.20(3H, t)1.55(3H, t)1.60(6H, s)                                                                 2970, 3000,                                                                          glass-like substance                               2.00-2.50(4H, m)2.50(3H, s)2.80(3H, s)                                                            1680, 1140,                                               3.30-3.60(2H, m)8.60-3.90(2H, m)                                                                  1300, 1190,                                               4.20(2H, q)7.10(H, s)7.40(H, s)                                                                   1390                                         10    10     1.05(3H, t)1.40-1.80(5H, m)1.55(6H, s)                                                            2900, 2980,                                                                          177.9-179.1                                        1.90-2.20(2H, m)2.25-2.50(2H, m)2.50                                                              1660, 1130,                                               (3H, s)2.80(3H, s)3.30-3.60(2H, m)                                                                1300, 1180,                                               3.65-3.90(2H, m)4.20(2H, q)7.10(H, s)                                                             1380                                                      7.40(H, s)                                                       11    11     0.80-1.00(3H, m)1.20-1.80(13H, m)                                                                 2880, 2950,                                                                          glass-like substance                               1.60(6H, s)1.90-2.20(2H, m)2.25-2.50                                                              1670, 1140,                                               (2H, m)2.50(3H, s)2.80(3H, s)3.30-3.60                                                            1300, 1380,                                               (2H, m)3.65-3.90(2H, m)4.20(2H, q)                                                                1390                                                      7.10(H, s)7.40(H, s)                                             12    12     1.50(3H, t)1.60(6H, s)2.20-2.60(2H, m)                                                            2950, 3000,                                                                          164.9-166.3                                        2.40(3H, s)2.50(3H, s)2.77(3H, s)                                                                 1670, 1130,                                               3.30-3.60(2H, m)4.20(2H, q)6.90(H, s)                                                             1300, 1180,                                               7.40(2H, d)7.48(H, s)7.90(2H, d)                                                                  1380                                         13    13     1.57(3H, t)1.60(6H, s)2.20-2.50(2H, m)                                                            2950, 1665,                                                                          172.3-174.2                                        2.40(3H, s)2.80(3H, s)3.30-3.57(2H, m)                                                            1130, 1290,                                               4.25(2H, q)6.95(H, s)7.40(H, s)                                                                   1200, 1380                                                8.40(4H, dd)                                                     14    14     1.50(3H, t)1.60(6H, s)2.20-2.50(2H, m)                                                            2950, 3000,                                                                          174.9-176.7                                        2.40(3H, s)2.78(3H, s)3.30-3.50(2H, m)                                                            1660, 1100,                                               3.90(3H, s)4.20(2H, q)6.90(H, s)7.10                                                              1290, 1180,                                               (2H, d)7.48(H, s)7.90(2H, d)                                                                      1380                                         15    15     1.50(3H, t)1.57(6H, s)2.25-2.60(2H, m)                                                            2980, 3000,                                                                          145.3-147.8                                        2.40(3H, s)2.78(3H, s)3.30-3.60(2H, m)                                                            1680, 1140,                                               4.20(2H, q)6.90(H, s)7.45(H, s)7.60                                                               1300, 1200,                                               (2H, d)8.00(2H, d)  1400                                         16    16     1.50(3H, t)1.53(6H, s)2.20-2.60(2H, m)                                                            2950, 3000,                                                                          182.1-184.5                                        2.30(3H, s)2.73(3H, s)2.88(3H, s)                                                                 1680, 1130,                                               3.30-3.60(2H, m)4.20(2H, q)6.80(H, s)                                                             1290, 1200,                                               7.25(H, s)7.30-8.00(4H, m)                                                                        1390                                         17    17     1.55(3H, t)1.60(6H, s)2.20-2.60(2H, m)                                                            2950, 3000,                                                                          181.8-185.8                                        2.30(3H, s)2.75(3H, m)3.28-3.50(2H, m)                                                            1670, 1130,                                               4.25(2H, q)6.90(H, s)7.25(H, s)                                                                   1290, 1190,                                               7.48-7.78(2H, m)7.85-8.00(H, m)                                                                   1400                                         18    18     1.45(3H, t)1.55(6H, s)2.20-2.60(2H, m)                                                            2950, 2980,                                                                          187.7-191.4                                        2.25(3H, s)2.45(3H, s)2.79(3H, s)                                                                 1660, 1120,                                               3.27-3.58(2H, m)4.00(2H, q)7.00(H, s)                                                             1160, 1290                                                7.60(H, s)                                                       19    19     1.22(3H, t)1.47(3H, t)1.60(6H, s)                                                                 2950, 3000,                                                                          178.0-179.6                                        2.20-2.70(4H, m)2.45(3H, s)2.80(3H, s)                                                            1660, 1110,                                               3.30-3.55(2H, m)4.00(2H, q)7.05(H, s)                                                             1300, 1200,                                               7.60(H, s)          1410                                         20    20     0.98(3H, t)1.20-2.00(7H, m)1.58(6H, s)                                                            2880, 2980,                                                                          glass-like substance                               2.20-2.70(4H, m)2.45(3H, s)2.78(3H, s)                                                            1670, 1140,                                               3.30-3.55(2H, m)4.00(2H, q)7.05(H, s)                                                             1300                                                      7.57(H, s)                                                       21    21     0.90(3H, t)1.10-1.90(11H, m)1.55(6H, s)                                                           2880, 2950,                                                                          glass-like substance                               2.20-2.70(4H, m)2.48(3H, m)2.75(3H, s)                                                            1660, 1120,                                               3.30-3.57(2H, m)4.00(2H, q)7.03(H, s)                                                             1800, 1190                                                7.55(H, s)                                                       22    22     1.42(3H, t)1.20-2.20(11H, m)1.55(6H, s)                                                           2950, 1660,                                                                          glass-like substance                               2.25-2.65(2H, m)2.42(3H, s)2.80(3H, s)                                                            1140, 1300,                                               3.30-3.55(2H, m)3.98(2H, q)7.05(H, s)                                                             1200                                                      7.60(H, s)                                                       23    23     1.55(3H, t)1.58(6H, s)2.15-2.50(2H, m)                                                            2950, 3000,                                                                          165.2-169.0                                        2.42(3H, s)2.75(3H, s)3.20-3.50(2H, m)                                                            1650, 1130,                                               4.10(2H, q)7.05(H, s)7.35-7.60(2H, m)                                                             1290, 1230                                                7.70(H, s)7.75-7.90(H, m)                                        24    24     1.48(3H, t)1.60(6H, s)2.20(3H, s)                                                                 2940, 2980,                                                                          glass-like substance                               2.28-2.50(2H, m)2.40(3H, s)2.80(3H, s)                                                            1640, 1130,                                               3.30-3.55(2H, m)4.20(2H, q)5.40(2H, s)                                                            1290, 1410                                                7.00(H, s)7.15(H, s)                                             25    25     1.50(6H, s)1.60(3H, t)2.20-2.50(2H, m)                                                            2950, 1650,                                                                          177.5-179.5                                        2.35(3H, s)2.75(3H, s)3.25-3.50(2H, m)                                                            1130, 1290,                                               4.30(2H, q)6.20(2H, s)6.95(H, s)                                                                  1190                                                      7.15(H, s)7.35-8.10(5H, m)                                       __________________________________________________________________________

Preparation Example 26

4,4,5,8-Tetramethyl-6-(1-methyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound 26) in an amount of 1.7 g (yield 78%) was obtained in the samemanner as in Preparation Example 1 except that1-methyl-5-hydroxypyrazole was used in place of the1-ethyl-5-hydroxypyrazole used in Preparation Example 1.

Preparation Example 27

0.80 Gram (2.2 mmol) of the4,4,5,8-tetramethyl-6-(1-methyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 26 was dissolved in 20 ml of methylenechloride. Then, 0.40 g (2.9 mmol) of potassium carbonate was dissolvedin 10 ml of water, and the resultant solution was added. Further, 0.43 g(3.0 mmol) of n-propanesulfonyl chloride and 0.05 g (0.2 mmol) ofbenzyltriethylammonium chloride were added. The mixture was allowed toreact at room temperature for 24 hours, and after the completion of thereaction, a methylene chloride layer was collected and dried overanhydrous sodium sulfate. Then, the solvent was distilled off underreduced pressure. The resultant oil was purified by silica gel columnchromatography to give 0.60 g (yield 59%) of4,4,5,8-tetramethyl-6-(1-methyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound 27).

Preparation Example 28

4,4,5,8-Tetramethyl-6-(1-methyl-5-p-toluenesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound 28) in an amount of 0.68 g (yield 64%) was obtained in thesame manner as in Preparation Example 27 except that p-toluenesulfonylchloride was used in place of the n-propanesulfonyl chloride used inPreparation Example 27.

Preparation Example 29

5-Chloro-4,4,8-trimethyl-6-(1-methyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxidein an amount of 0.52 g (yield 50%) was obtained in the same manner as inPreparation Example 1 except that5-chloro-4,4,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide wasused in place of the 4,4,5,8-tetramethylthiochroman-6-carboxylicacid-1,1-dioxide used in Preparation Example 1.

Table 5 shows the structural formulae and yields of Compounds obtainedin Preparation Examples 26 to 29. Table 6 shows the physical propertiesof the Compounds.

                                      TABLE 5                                     __________________________________________________________________________    Pre.                                                                             reaction            Comp.                                                                             Structural          Yield                          Ex.                                                                              reagent             No. formula             (%)                            __________________________________________________________________________    26                                                                                ##STR96##          26                                                                                 ##STR97##          78                             27                                                                                ##STR98##          27                                                                                 ##STR99##          59                             28                                                                                ##STR100##         28                                                                                 ##STR101##         64                             29                                                                                ##STR102##         29                                                                                 ##STR103##         50                             __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________                 N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane        I.R. (cm.sup.-1)                                          Solvent: deutero    KBr tablet                                                                            Melting point                        Pre. Ex.                                                                            Comp. No.                                                                            chloroform          method  (°C.)                         __________________________________________________________________________    26    26     1.60(6H, s)2.25-2.45(2H, m)2.50(3H, s)                                                            not measured                                                                          glass-like substance                              2.70(3H, s)3.35-3.50(2H, m)3.70(3H, s)                                        4.40(H,)7.10(H, s)7.50(H, s)                                     27    27     1.20(3H, t)1.55(6H, s)1.90-2.40(4H, m)                                                            2940, 2970                                                                            191.2-194.3                                       2.43(3H, s)2.80(3H, s)3.35-3.50(2H, m)                                                            1670                                                      3.60-3.80(2H, m)3.90(3H, s)7.05(H, s)                                                             1165, 1280                                                7.40(H, s)          1380                                         28    28     1.53(6H, s)2.25-2.45(2H, m)2.40(3H, s)                                                            2940, 2970                                                                            187.7-191.2                                       2.48(3H, s)2.74(3H, s)3.35-3.50(2H, m)                                                            1640                                                      3.82(3H, s)6.90(H, s)7.29(H, s)                                                                   1160, 1285                                                7.65(4H, dd)        1365                                         29    29     1.20(3H, t)1.70(6H, s)2.20-2.45(2H, m)                                                            2950, 3000                                                                            glass-like substance                              2.60(3H, s)3.30-3.60(2H, m)4.00(2H, q)                                                            1620, 1320                                                6.95(H, s)7.05(H, s)*                                                                             1130                                         __________________________________________________________________________     *solvent: deutero acetone                                                

Preparation Example 30

2.7 Grams (7.1 mmol) of the4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 6 was dissolved in 20 ml of methylenechloride, and a solution of 1.5 g of potassium carbonate in 20 ml ofmethylene chloride was added. Further, 0.76 g (10.5 mmol) ofn-propanesulfonyl chloride was dissolved in 10 ml of methylene chloride,and the resultant solution was added. Then, 50 mg ofbenzyltriethylammonium chloride was added. The mixture was allowed toreact at room temperature for 7 hours, and then a methylene chloridelayer was separated. The methylene chloride layer was dried over sodiumsulfate, and then the solvent was distilled off under reduced pressure.When the resultant oily substance was washed with an ethylacetate/n-hexane mixed solvent (1:2 (V/V)) to form a solid, and themixture was filtered to give 1.26 g (yield 74%) of4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 30).

Preparation Examples 31-33

Compounds 31, 32 and 33 shown in the right column of Table 7 wereobtained substantially in the same manner as in Preparation Example 30except that reaction reagents shown in the left column of Table 7 wereused in place of the n-propanesulfonyl chloride used in PreparationExample 30.

Table 7 shows the reaction reagents used in Preparation Examples 30 to33 and the structural formulae and yields of Compounds obtained inPreparation Examples 30 to 33. Table 8 shows the physical properties ofthe Compounds.

                                      TABLE 7                                     __________________________________________________________________________    Pre.                                                                             reaction     Comp.                                                                             Structural           Yield                                Ex.                                                                              reagent      No. formula              (%)                                  __________________________________________________________________________    30                                                                                ##STR104##  30                                                                                 ##STR105##          74                                   31                                                                                ##STR106##  31                                                                                 ##STR107##          77                                   32                                                                                ##STR108##  32                                                                                 ##STR109##          50                                   33                                                                                ##STR110##  33                                                                                 ##STR111##          57                                   __________________________________________________________________________

                  TABLE 8                                                         ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform         IR (cm.sup.-1)                              ______________________________________                                        30    30       1.14(3H, t)1.57(6H, s)                                                                           3000, 2960                                                 1.97(3H, s)1.8˜2.1(2H, m)                                                                  1670                                                       2.25˜2.5(2H, m)2.46(3H, s)                                                                 1380, 1300                                                 2.77(3H, s)3.25˜3.5(4H, m)                                                                 1190, 1130                                                 3.81(3H, s)7.01(H, s)                                          31    31       1.55(6H, s)2.16(3H, s)                                                                           2950                                                       2.25˜2.45(2H, m)2.43(3H, s)                                                                1650, 1400                                                 2.47(3H, s)        1295                                                       2.72(3H, s)3.36˜3.5(2H, m)                                                                 1185, 1140                                                 3.66(3H, s)                                                                   6.90(H, s)7.50(4H, dd)                                         32    32       1.57(6H, s)1.91(3H, s)                                                                           2970                                                       2.3˜2.5(2H, m)                                                                             1660                                                       2.46(3H, s)2.78(3H, s)                                                                           1390, 1300                                                 3.3˜3.5(2H, m)3.33(3H, s)                                                                  1200, 1140                                                 3.82(3H, s)7.01(H, s)                                          33    33       1.52(6H, s)2.03(3H, s)                                                                           2950                                                       2.25˜2.5(2H, m)2.40(3H, s)                                                                 1660                                                       2.68(3H, s)2.71(3H, s)                                                                           1380                                                       3.3˜3.5(2H, m)3.63(3H, s)                                                                  1285                                                       6.81(H, s)7.35˜7.78(4H, m)                                                                 1190, 1140                                  ______________________________________                                    

Preparation Example 34

1.0 Gram (2.7 mmol) of the4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 6 was dissolved in 10 ml of1,2-dichloroethane, and further, 0.27 g (3.5 mmol) of pyridine and 10 mgof dimethylaminopyridine were added. Then, 0.64 g (3.5 mmol) of4-nitrobenzoyl chloride was dropwise added, and the mixture was allowedto react at room temperature for 3 hours. To the reaction mixture wasadded 50 ml of water and then an organic layer was separated. Theorganic layer was consecutively washed with 10% hydrochloric acid, witha saturated sodium bicarbonate aqueous solution and with a saturatedsodium chloride aqueous solution, and the solvent was distilled offunder reduced pressure. The resultant solid was washed with ethylacetate and filtered to give 0.86 g (yield 62%) of4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(4-nitrophenyl)sulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 34) in the form of a white crystal.

Preparation Examples 35-39

Compounds 35, 36, 37, 38 and 39 shown in the right column of Table 9were obtained substantially in the same manner as in Preparation Example34 except that reaction reagents shown in the left column of Table 9were used in place of the nitrobenzoyl chloride used in PreparationExample 34.

Table 9 shows the reaction reagents used in Preparation Examples 34 to39 and the structural formulae and yields of Compounds obtained inPreparation Examples 34 to 39. Table 10 shows the physical properties ofthe Compounds.

Preparation Example 40

1.0 Gram (2.7 mmol) of the4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 6 was dissolved in 10 ml oftetrahydrofuran, and further, 0.27 g (3.5 mmol) of pyridine and 90 mg ofpotassium iodide were added. Then, 0.63 g (3.5 mmol) of ethyl2-bromopropionate was added, and the mixture was refluxed under heat for7 hours. The reaction mixture was cooled to room temperature, and thesolvent was distilled off under reduced pressure. The resultant residuewas extracted by adding ethyl acetate, and the extract was consecutivelywashed with 10% hydrochloric acid, with a saturated sodium bicarbonateaqueous solution and with a saturated sodium chloride aqueous solution,and the solvent was distilled off under reduced pressure to give 0.57 g(yield 45%) of4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(1-ethoxycarbonyl)ethoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 40).

Preparation Example 41

Compound 41 shown in the right column of Table 9 was obtainedsubstantially in the same manner as in Preparation Example 40 exceptthat a reaction reagent shown in the left column of Table 9 was used inplace of the ethyl 2-bromopropionate used in Preparation Example 40.

Table 9 shows the reaction reagents used in Preparation Examples 40 and41 and the structural formulae and yields of Compounds obtained inPreparation Examples 40 and 41. Table 10 shows the physical propertiesof the Compounds.

                                      TABLE 9                                     __________________________________________________________________________    Pre.                                                                             reaction Comp.                                                                             Structural           Yield                                    Ex.                                                                              reagent  No. formula              (%)                                      __________________________________________________________________________    34                                                                                ##STR112##                                                                            34                                                                                 ##STR113##          62                                       35                                                                                ##STR114##                                                                            35                                                                                 ##STR115##          56                                       36                                                                                ##STR116##                                                                            36                                                                                 ##STR117##          81                                       37                                                                                ##STR118##                                                                            37                                                                                 ##STR119##          86                                       38                                                                                ##STR120##                                                                            38                                                                                 ##STR121##          81                                       39                                                                                ##STR122##                                                                            39                                                                                 ##STR123##          46                                       40                                                                                ##STR124##                                                                            40                                                                                 ##STR125##          45                                       41                                                                                ##STR126##                                                                            41                                                                                 ##STR127##          31                                       __________________________________________________________________________

                  TABLE 10                                                        ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform         IR (cm.sup.-1)                              ______________________________________                                        34    34       1.37(6H, s)2.05˜2.2(2H, m)                                                                 2930                                                       2.38(3H, s)2.44(3H, s)                                                                           1760, 1640                                                 2.62(3H, s)        1525                                                       3.07˜3.2(2H, m)                                                                            1280, 1240                                                 3.66(3H, s)6.95(H, s)                                                         8.12(4H, dd)                                                   35    35       1.35(6H, s)        3000, 2970                                                 2.04˜2.24(2H, m)2.39(6H, s)                                                                1780, 1660                                                 2.72(3H, s)        1300, 1230                                                 3.16˜3.29(2H, m)                                                                           1235                                                       3.66(3H, s)                                                                   6.99(H, s)7.36˜7.53(3H, m)                               36    36       1.55(6H, s)        2950                                                       2.0˜2.13(2H, m)2.34(3H, s)                                                                 1770, 1650                                                 2.52(3H, s)2.71(3H, s)                                                                           1290, 1240                                                 3.03˜3.17(2H, m)3.61(3H, s)                                             7.00(H, s)7.48˜7.7(5H, m)                                37    37       1.16˜1.88(11H, m)                                                                          2970                                                       1.56(6H, s)2.31(3H, s)                                                                           1795, 1655                                                 2.41(3H, s)2.75(3H, s)                                                                           1300                                                       2.25˜2.45(2H, m)                                                                           1135                                                       3.33˜3.47(2H, m)3.55(3H, s)                                             6.94(H, s)                                                     38    38       1.32(3H, t)1.57(6H, s)                                                                           2970                                                       2.24˜2.5(2H, m)                                                                            1795, 1670                                                 2.27(3H, s)2.42(3H, s)                                                                           1295, 1255                                                 2.75(3H, s)        1130                                                       3.33˜3.47(2H, m)3.64(3H, s)                                             4.16(4H, q)6.94(H, s)                                          39    39       1.55(6H, s)        2950                                                       2.25˜2.45(2H, m)2.43(6H, s)                                                                1755, 1640                                                 2.61(3H, s)2.74(3H, s)                                                                           1280, 1140                                                 2.83(3H, s)3.3˜3.5(2H, m)                                               3.58(3H, s)                                                                   6.99(H, s)                                                     40    40       1.26(3H, s)1.55(6H, s)                                                                           2930                                                       1.60(3H, s)1.67(3H, s)                                                                           1740                                                       2.3˜2.5(2H, m)2.42(3H, s)                                                                  1630, 1500                                                 2.76(3H, s)3.33˜3.5(2H, m)                                                                 1285, 1120                                                 3.76(3H, s)4.19(2H, q)                                                        5.40(H, q)6.95(H, s)                                           41    41       1.56(6H, s)1.64(3H, s)                                                                           2970                                                       1.70(3H, s)2.3˜2.45(2H, m)                                                                 1775, 1645                                                 2.37(3H, s)2.76(3H, s)                                                                           1295, 1220                                                 3.34˜3.48(2H, m)                                                                           1130                                                       3.77(3H, s)3.78(3H, s)                                                        5.02(2H, s)6.96(H, s)                                          ______________________________________                                    

Preparation Example 42

1.0 Gram (2.7 mmol) of the4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 6 was dissolved in 10 ml of1,2-dichloroethane, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g(3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg ofbenzyltriethylammonium chloride were added. The mixture was allowed toreact at room temperature for 3 hours. The extraction of the reactionmixture was carried out by adding ethyl acetate, and the extract wasconsecutively washed with 10% hydrochloric acid, with a saturated sodiumbicarbonate aqueous solution and with a saturated sodium chlorideaqueous solution. The solvent was removed by filtration under reducedpressure, and the resultant oily substance was washed with an ethylacetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixturewas filtered to give 1.0 g (yield 80%) of4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 42).

Table 11 shows the reaction reagent used in Preparation Example 42 andthe structural formula and yield of the Compound obtained in PreparationExample 42. Table 12 shows the physical properties of the Compound.

                                      TABLE 11                                    __________________________________________________________________________    Pre.                                                                             reaction                                                                              Comp.                                                                             Structural           Yield                                     Ex.                                                                              reagent No. formula              (%)                                       __________________________________________________________________________    42                                                                                ##STR128##                                                                           42                                                                                 ##STR129##          80                                        __________________________________________________________________________

                  TABLE 12                                                        ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform         IR (cm.sup.-1)                              ______________________________________                                        42    42       1.28(6H, s)2.35(3H, s)                                                                           2970                                                       2.04˜2.19(2H, m)                                                                           1780, 1665                                                 2.43(3H, s)2.73(3H, s)                                                                           1300, 1260                                                 3.08˜3.22(2H, m)3.63(3H, s)                                                                1135                                                       6.99(H, s)7.47˜7.54(2H, m)                                              8.84˜8.91(2H, m)                                         ______________________________________                                    

Preparation Example 43

A 100-ml eggplant type flask was charged with 1.0 g (3.9 mmol) of the3,3,4,7-tetramethyl-2-hydrobenzo[b]thiophene-5-carboxylicacid-1,1-dioxide obtained in Intermediate Preparation Example 5, 0.48 g(4.3 mmol, 1.1 equivalents) of 1-ethyl-5-hydroxypyrazole and 100 ml oft-amyl alcohol. 1.04 g (5.0 mmol, 1.3 equivalents) ofN,N'-dicyclohexylcarbodiimide (DCC) was added as a dehydrating agent,and the mixture was allowed to react at room temperature for 4 hours. Tothe reaction mixture was added 0.53 g (3.9 mmol, 1 equivalent) ofpotassium carbonate as a base, and the mixture was allowed to reactfurther at 100° C. for 2 hours. After the completion of the reaction,the solvent was distilled off, and the residue was liquid-separated byadding 50 ml of ethyl acetate and 50 ml of water. The resultant aqueouslayer was neutralized with 5% hydrochloric acid and then extracted withethyl acetate, and the resultant organic layer was washed with asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. The solvent was distilled off to give 0.8 g (yield 57%)of3,3,4,7-tetramethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide(Compound No. 43).

Preparation Example 44

A 50-ml eggplant type flask was charged with 0.76 g (2.8 mmol) of4,5,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide, 0.35 g (2.1mmol, 1.1 equivalents) of 1-ethyl-5-hydroxypyrazole and 5 ml of t-amylalcohol, and a solution of 0.70 g (3.4 mmol, 1.2 equivalents) ofN,N'-dicyclohexylcarbodiimide (DCC) in 5 ml of t-amyl alcohol was addedat room temperature. The mixture was allowed to react at roomtemperature for 2 hours, then, 0.58 g (2.8 mmol, 1.5 equivalents) ofpotassium carbonate was added, and the mixture was allowed to react at100° C. for 6 hours. The solvent was distilled off, the residue wasdistributed into 30 ml of water and 30 ml of ethyl acetate, and a DCCurea material as an insoluble material was separated by filtration. Anorganic layer was extracted with 10 ml of a 5% potassium carbonateaqueous solution twice. The aqueous layers were combined and acidifiedwith concentrated hydrochloric acid and thereafter extracted with ethylacetate. The extract was washed with a saturated sodium chloride aqueoussolution and dried over sodium sulfate, and the solvent was distilledoff to give 0.77 g of a crude product. The crude product wasrecrystallized from ethanol to give 0.52 g (yield 51%) of4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 44).

Preparation Example 45

0.9 g (3.2 mmol) of the 4-ethyl-5,8-dimethylthiochroman-6-carboxylicacid-1,1-dioxide obtained in Intermediate Preparation Example 7, 0.43 g(3.8 mmol) of 1-ethyl-5-hydroxypyrazole and 0.79 g (3.8 mmol) of DCCwere added to 5 ml of tert-amyl alcohol, and the mixture was allowed toreact at room temperature for 2.5 hours. Thereafter, 0.31 g (2.2 mmol)of potassium carbonate was added, and the mixture was allowed to reactat 80° C. for 4 hours. The reaction mixture was cooled to roomtemperature, and the solvent was distilled off under reduced pressure. A2% sodium carbonate aqueous solution was added to the residue todissolve the residue therein, and insolubles were filtered off. Theresultant aqueous solution was washed with ethyl acetate, and 12Nhydrochloric acid was added so that the mixture had a pH of 1. Theresultant oily substance was extracted with ethyl acetate. An ethylacetate layer was separated and washed with a saturated sodium chlorideaqueous solution, and the solvent was distilled off under reducedpressure to give 1.2 g (yield 100%) of4-ethyl-5,8-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 45).

Preparation Example 46

A 50-ml eggplant type flask was charged with 2.38 g (9.4 mmol) of3,4,7-trimethyl-2-hydrobenzo[b]thiophene-5-carboxylic acid-1,1-dioxide,1.15 g (10.3 mmol, 1.1 equivalents) of 1-ethyl-5-hydroxypyrazole and 10ml of t-amyl alcohol, and a solution of 2.31 g (12.2 mmol, 1.3equivalents) of DCC in 5 ml of t-amyl alcohol was added at roomtemperature. The mixture was allowed to react at room temperature for 2hours, then 1.68 g (12.2 mmol, 3 equivalents) of potassium carbonate wasadded, and the mixture was allowed to react at 100° C. for 6 hours. Thesolvent was distilled off, the residue was distributed into 50 ml ofwater and 50 ml of ethyl acetate, and a DCC urea material as aninsoluble one was filtered off. An organic layer was extracted with 15ml of a 5% potassium carbonate aqueous solution twice, an aqueous layerwas added. The aqueous layers were collected and acidified withconcentrated hydrochloric acid and thereafter extracted with ethylacetate. The extract was washed with a saturated sodium cTahlorideaqueous solution and dried over sodium sulfate, and the solvent wasdistilled off to give 2.34 g of a crude product. The crude product wasrecrystallized from ethanol to give 1.39 g (yield 42%) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide(Compound No. 46).

Table 13 shows the structural formula of the starting materials used inPreparation Examples 43˜46 and Compounds obtained in these PreparationExamples together with their yields, and Table 14 shows physicalproperties of Compounds obtained in Preparation Examples 43˜46.

                                      TABLE 13                                    __________________________________________________________________________    Pre.                                                                             starting       Comp.                                                                             Structural            Yield                             Ex.                                                                              material       No. formula               (%)                               __________________________________________________________________________    43                                                                                ##STR130##    43                                                                                 ##STR131##           57                                44                                                                                ##STR132##    44                                                                                 ##STR133##           51                                45                                                                                ##STR134##    45                                                                                 ##STR135##           100                               46                                                                                ##STR136##    46                                                                                 ##STR137##           42                                __________________________________________________________________________

                  TABLE 14                                                        ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform        IR (cm.sup.-1)                               ______________________________________                                        43    43       1.46(3H, t)1.67(6H, s)                                                                          3000                                                        2.45(3H, s)2.64(3H, s)                                                                          1660                                                        3.37(2H, s)4.08(2H, q)                                                                          1305                                                        4.40(H, s)        1100                                                        7.24(H, s)7.32(H, s)                                           44    44       1.37(3H, d)1.46(3H, t)                                                                          2980, 2950                                                  2.1˜3.9(5H, m)2.35(3H, s)                                                                 1625                                                        2.76(3H, s)       1300, 1280                                                  4.08(2H, q)       1125                                                        6.0(H, s)                                                                     7.19(H, s)7.32(H, s)                                           45    45       1.06(3H, t)1.46(3H, t)                                                                          not measured                                                1.6˜1.9(2H, m)2.32(3H, s)                                               2.35˜2.65(2H, m)                                                        2.76(3H, s)2.9˜3.8(3H, m)                                               4.07(2H, q)4.94(H, s)                                                         7.19(H, s)7.32(H, s)                                           46    46       1.47(6H, t)1.49(3H, d)                                                                          2980                                                        2.36(3H, s)2.65(3H, s)                                                                          1640                                                        3.1˜3.9(3H, m)4.09(2H, q)                                                                 1295, 1175                                                  6.39(H, s)7.29(H, s)                                                                            1120                                                        7.35(H, s)                                                     ______________________________________                                    

Preparation Example 47

Step (1)

A 100-ml eggplant type flask was charged with 0.96 g (4.4 mmol) of the5,8-dimethyl-3,4-dehydrothiochroman-6-carboxylic acid obtained inIntermediate Preparation Example 5, 0.54 g (4.8 mmol, 1,1 equivalents)of 1-ethyl-5-hydroxypyrazole and 10 ml of dichloromethane, and 1.08 g(5.2 mmol, 1.2 equivalents) of DCC as a dehydrating agent was added. Themixture was allowed to react at room temperature for 2 hours. A DCC ureamaterial was filtered off, and the filtrate was concentrated and thenpurified by silica gel column chromatography (developer solvent: ethylacetate:n-hexane, 1:1 mixture). To 0.81 g (2.6 mmol) of the esterintermediate obtained by the above purification were added 0.53 g (3.9mmol, 1.5 equivalents) of potassium carbonate as a base and 2.0 ml of1,4-dioxane, and the mixture was allowed to react further at 120° C. for2 hours. After the completion of the reaction, the solvent was distilledoff, and the residue was liquid-separated by adding 50 ml of ethylacetate and 50 ml of water. The resultant aqueous layer was neutralizedwith 5% hydrochloric acid and then extracted with ethyl acetate. Theresultant organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate, and thesolvent was distilled off to give 0.63 g (yield 57%) of5,8-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,4-dehydrothiochroman(Compound No. 47-1).

Step (2)

A 30-ml eggplant type flask was charged with 75 mg (0.24 mmol) of the5,8-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,4-dehydrothiochromanobtained in the above step (1), 7 mg of platinum oxide and 3 ml ofethanol, and the mixture was subjected to hydrogenation at roomtemperature under atmospheric pressure. After the reaction was carriedout for 8 hours, the platinum oxide was filtered off, and the ethanolwas distilled off to give 67 mg (yield 88%) of5,8-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman(Compound No. 47-2). The yield through the steps (1) and (2) was 50%.

Preparation Example 48

5-Methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 48) was obtained essentially in the same manner as inPreparation Example 47 except that5-methyl-3,4-dehydrothiochroman-6-carboxylic acid-1,1-dioxide obtainedin Intermediate Preparation Example 10 was used in place of the5,8-dimethyl-3,4-dehydrothiochroman-6-carboxylic acid in PreparationExample 47.

Table 15 shows the structural formula of the starting materials used inPreparation Examples 47˜48 and Compounds obtained in these PreparationExamples together with their yields, and Table 16 shows physicalproperties of Compounds obtained in Preparation Examples 47˜48.

                                      TABLE 15                                    __________________________________________________________________________    Pre.                                                                              starting            Comp.                                                                             Structural          Yield                         Ex. material            No. formula             (%)                           __________________________________________________________________________    47 step 1                                                                          ##STR138##         47-1                                                                               ##STR139##         57                            47 step 2                                                                          ##STR140##         47-2                                                                               ##STR141##         88                            48                                                                                 ##STR142##         48                                                                                 ##STR143##         62                            __________________________________________________________________________

                  TABLE 16                                                        ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform        IR (cm.sup.-1)                               ______________________________________                                        47    47-1     1.45(3H, t)2.32(3H, s)                                                                          not measured                                 step 1         2.37(3H, s)3.38(2H, d)                                                        4.07(2H, q)5.9˜6.3(1H, m)                                               6.79(1H, d)7.13(1H, s)                                                        7.45(1H, s)                                                    47    47-2     1.43(3H, t)2.0˜2.6(8H, m)                                                                 not measured                                 step 2         2.7˜3.1(2H, m)                                                          4.07(2H, q)                                                                   7.11(H, s)7.45(H, s)                                           48    48       1.43(3H, t)2.20(3H, s)                                                                          not measured                                                2.35˜2.7(3H, m)                                                         2.8˜3.0(2H, m)                                                          3.25˜3.45(2H, m)                                                        4.0(2H, q)7.36(H, d)                                                          7.55(H, s)7.89(H, d)                                           ______________________________________                                    

Preparation Example 49

A 100-ml eggplant type flask was charged with 0.4 g (1.1 mmol) of the3,3,4,7-tetramethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide(Compound No. 43) obtained in preparation Example 43, 10 ml ofdichloromethane, 10 ml of water and 0.2 g (1.4 mmol) of potassiumcarbonate, and 0.19 g (1.3 mmol, 1.2 equivalents) of n-propanesulfonylchloride was dropwise added at room temperature. 50 mg ofbenzyltriethylammonium chloride (BTEAC) was added, and the mixture wasallowed to react at the above temperature for 2 hours. Then, thereaction mixture was liquid-separated. The resultant aqueous layer wasextracted with dichloromethane, and the resultant organic layer waswashed with a saturated sodium chloride aqueous solution and then driedover anhydrous sodium sulfate. The solvent was distilled off to give0.45 g (yield 87%) of3,3,4,7-tetramethyl-5-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide(Compound No. 49).

Preparation Example 50

A 100-ml eggplant type flask was charged with 0.4 g (1.1 mmol) of3,3,4,7-tetramethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxideobtained in said Preparation Example 43, 10 ml of dichloromethane, 10 mlof water and 0.2 g (1.4 mmol, 1.3 equivalents) of potassium carbonate,and 0.25 g (1.3 mmol, 1.2 equivalents) of p-toluenesulfonyl chloride wasdropwise added at room temperature. 50 mg of benzyltriethylammoniumchloride (BTEAC) was added, and the mixture was allowed to react at theabove temperature for 2 hours and then liquid-separated. The resultantaqueous layer was extracted with dichloromethane, and the resultantorganic layer was washed with a saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 0.52 g (yield 91%) of3,3,4,7-tetramethyl-5-(1-ethyl-5-p-toluenesulfonyloxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-5-carboxylicacid-1,1-dioxide (Compound No. 50).

Preparation Example 51

A 30-ml eggplant type flask was charged with 0.25 g (0.69 mmol) of4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide,5 ml of dichloromethane, 5 ml of water and 0.09 g (0.69 mmol, 1equivalent) of potassium carbonate, and 0.11 g (0.76 mmol, 1.1equivalents) of n-propanesulfonyl chloride was dropwise added withstirring at room temperature. 5 mg of benzyltriethylammonium chloride(BTEAC) was added, and the mixture was allowed to react at the abovetemperature for 2 hours and then liquid-separated. An aqueous layer wasextracted with dichloromethane. An organic layer was washed with asaturated sodium chloride aqueous solution and dried over sodiumsulfate. The solvent was distilled off to give 0.35 g of a crudeproduct, which was recrystalized from ethanol to give 0.31 g (yield 95%)of4,5,8-trimethyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 51).

Preparation Example 52

A 30-ml eggplant type flask was charged with 0.18 g (0.50 mmol) of4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide,5 ml of dichloromethane, 5 ml of water and 0.07 g (0.50 mmol, 1equivalent) of potassium carbonate, and a solution of 0.10 g (0.55 mmol,1.1 equivalents) of p-toluenesulfonyl chloride in 1 ml ofdichloromethane was dropwise added with stirring at room temperature. 5mg of benzyltriethylammonium chloride (BTEAC) was added, and the mixturewas allowed to react at the above temperature for 2 hours and thenliquid-separated. An aqueous layer was extracted with dichloromethane.An organic layer was washed with a saturated sodium chloride aqueoussolution and dried over sodium sulfate. The solvent was distilled off togive 0.30 g of a crude product, which was then recrystalized fromethanol to give 0.20 g (yield 77%) of4,5,8-trimethyl-6-(1-ethyl-5-p-toluenesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 52).

Preparation Example 53

A 30-ml eggplant type flask was charged with 0.30 g (0.86 mmol) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide,5 ml of dichloromethane, 5 ml of water and 0.12 g (0.69 mmol, 0.8equivalent) of potassium carbonate, and 0.16 g (0.95 mmol, 1.1equivalents) of n-propanesulfonyl chloride was dropwise added withstirring at room temperature. 5 mg of benzyltriethylammonium chloride(BTEAC) was added, and the mixture was allowed to react at the abovetemperature for 2 hours and then liquid-separated. An aqueous layer wasextracted with dichloromethane. An organic layer was washed with asaturated sodium chloride aqueous solution and dried over sodiumsulfate. The solvent was distilled off to give 0.40 g of a crudeproduct, and the crude product was recrystallized from ethanol to give0.31 g (yield 79%) of3,4,7-trimethyl-5-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)-2-hydrobenzo[b]thiophenecarbonyl-1,1-dioxide(Compound No. 5.3).

Preparation Example 54

A 30-ml eggplant type flask was charged with 0.25 g (0.72 mmol) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide,5 ml of dichloromethane, 5 ml of water and 0.10 g (0.72 mmol, 1equivalent) of potassium carbonate, and a solution of 0.15 g (0.72 mmol,1.1 equivalents) of p-toluenesulfonyl chloride in 1 ml ofdichloromethane was dropwise added with stirring at room temperature. 5mg of benzyltriethylammonium chloride (BTEAC) was added, and the mixturewas allowed to react at the above temperature for 2 hours and thenliquid-separated. An aqueous layer was extracted with dichloromethane.An organic layer was washed with a saturated sodium chloride aqueoussolution and dried over sodium sulfate. The solvent was distilled off togive 0.34 g of a crude product, and the crude product was recrystallizedfrom ethanol to give 0.29 g (yield 80%) of3,4,7-trimethyl-5-(1-ethyl-p-toluenesulfonyloxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide(Compound No. 54).

Preparation Example 55

A 30-ml eggplant type flask was charged with 0.30 g (0.86 mmol) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide,5 ml of dichloromethane, 5 ml of water and 0.12 g (0.69 mmol, 0.8equivalent) of potassium carbonate, and 0.12 g (0.95 mmol, 1.1equivalents) of ethanesulfonyl chloride was dropwise added with stirringat room temperature. 5 mg of benzyltriethylammonium chloride (BTEAC) wasadded, and the mixture was allowed to react at the above temperature for2 hours and then liquid-separated. An aqueous layer was extracted withdichloromethane. An organic layer was washed with a saturated sodiumchloride aqueous solution and dried over sodium sulfate. The solvent wasdistilled off to give 0.35 g of a crude product, and the crude productwas recrystallized from ethanol to give 0.24 g (yield 63%) of3,4,7-trimethyl-5-(1-ethyl-5-ethanesulfonyoxypyrazol-4-yl)-2-hydrobenzo[b]thiophenecarbonyl-1,1-dioxide(Compound No. 55).

Preparation Example 56

A 30-ml eggplant type flask was charged with 0.30 g (0.86 mmol) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide,5 ml of dichloromethane and 0.09 g (1.1 mmol, 1.3 equivalents) ofpyridine. While the mixture was stirred with cooling with ice, 0.10 g(0.95 mmol, 1.1 equivalents)of isobutyric acid chloride was dropwiseadded. The mixture was stirred under cooling with ice for 30 minutes andthen allowed to react at room temperature for 2 hours. The reaction wasterminated by adding 5 ml of water, and then an aqueous layer wasextracted with dichloromethane. An organic layer was washed with 5%hydrochloric acid, with a 5% potassium carbonate aqueous solution andthen with a saturated sodium chloride aqueous solution and dried oversodium sulfate. The solvent was distilled off to give 0.28 g of a crudeproduct, and the crude product was recrystallized from ethanol to give0.27 g (yield 75%) of3,4,7-trimethyl-5-(1-ethyl-5-isopropylcarbonyloxypyrazol-4-yl)-2-hydrobenzo[b]-thiophenecarbonyl-1,1-dioxide(Compound No. 56).

Preparation Example 57

A 30-ml eggplant type flask was charged with 0.24 g (0.69 mmol) of3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]thiophene-1,1-dioxide,5 ml of dichloromethane and 0.07 g (0.89 mmol, 1.3 equivalents) ofpyridine. While the mixture was stirred with cooling with ice, 0.11 g(0.76 mmol, 1.1 equivalents) of cyclohexanecarboxylic acid chloride wasdropwise added. The mixture was stirred under cooling with ice for 30minutes and then allowed to react at room temperature for 2 hours. Thereaction was terminated by adding 5 ml of water, and then an aqueouslayer was extracted with dichloromethane. An organic layer was washedwith 5% hydrochloric acid, with a 5% potassium carbonate aqueoussolution and then with a saturated sodium chloride aqueous solution anddried over sodium sulfate. The solvent was distilled off to give 0.35 gof a crude product, and the crude product was recrystallized fromethanol to give 0.32 g (yield 100%) of3,4,7-trimethyl-5-(1-ethyl-5-carbonyloxypyrazol-4-yl)-2-hydrobenzo[b]thiophenecarbonyl-1,1-dioxide(Compound No. 57).

Preparation Example 58

A 30-ml eggplant type flask was charged with 0.30 g (0.86 mmol) of5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide,25 ml of dichloromethane, 5 ml of water and 0.14 g (0.86 mmol, 1equivalent) of potassium carbonate. While the mixture was stirred atroom temperature, 0.14 g (0.95 mmol, 1.1 equivalents) ofn-propanesulfonyl chloride was dropwise added. 5 mg ofbenzyltriethylammonium chloride (BTEAC) was added, and the mixture wasallowed to react at the above temperature for 2 hours and thenliquid-separated. An aqueous layer was extracted with dichloromethane.An organic layer was washed with a saturated sodium chloride aqueoussolution and dried over sodium sulfate. The solvent was distilled off togive 0.2 g of a crude product, and the crude product was recrystallizedfrom ethanol to give 0.18 g (yield 48%) of5-methyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazole-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 58).

Preparation Example 59

5 ml of dichloromethane, 5 ml of water and 0.10 g (0.72 mmol, 1equivalent) of potassium carbonate were added to 0.26 g (0.75 mmol) of5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxidein a 30-ml eggplant type flask. While the mixture was stirred at roomtemperature, a solution of 0.16 g (0.82 mmol, 1.1 equivalents) ofp-toluenesulfonyl chloride in 1 ml of dichloromethane was dropwise addedat room temperature. 5 mg of benzyltriethylammonium chloride (BTEAC) wasadded, and the mixture was allowed to react at the above temperature for2 hours and then liquid-separated. An aqueous layer was extracted withdichloromethane. An organic layer was washed with a saturated sodiumchloride aqueous solution and dried over sodium sulfate. The solvent wasdistilled off to give 0.24 g of a crude product, and the crude productwas recrystallized from ethanol to give 0.14 g (yield 92%) of5-methyl-6-(1-ethyl-p-toluenesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 59).

Preparation Example 60

5-Methyl-6-(1-ethyl-5-cyclohexylcarbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide(Compound No. 60) was obtained essentially in the same manner as inPreparation Example 57 except that the5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxideobtained in Preparation Example 48 was used in place of the3,4,7-trimethyl-5-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-2-hydrobenzo[b]-thiophene-1,1-dioxidein Preparation Example 57.

Tables 17˜19 show the structural formulae of reaction reagents used inPreparation Examples 49˜60 and Compounds obtained in these PreparationExamples together with their yields, and Tables 20˜23 show physicalproperties of Compounds obtained in Preparation Examples 49˜60.

                                      TABLE 17                                    __________________________________________________________________________    Pre.                                                                             reaction     Comp.                                                                             Structural            Yield                               Ex.                                                                              reagent      No. formula               (%)                                 __________________________________________________________________________    49                                                                                ##STR144##  49                                                                                 ##STR145##           87                                  50                                                                                ##STR146##  50                                                                                 ##STR147##           91                                  51                                                                                ##STR148##  51                                                                                 ##STR149##           95                                  52                                                                                ##STR150##  52                                                                                 ##STR151##           77                                  __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________    Pre.                                                                             reaction     Comp.                                                                             Structural          Yield                                 Ex.                                                                              reagent      No. formula             (%)                                   __________________________________________________________________________    53                                                                                ##STR152##  53                                                                                 ##STR153##         79                                    54                                                                                ##STR154##  54                                                                                 ##STR155##         80                                    55                                                                                ##STR156##  55                                                                                 ##STR157##         63                                    56                                                                                ##STR158##  56                                                                                 ##STR159##         75                                    57                                                                                ##STR160##  57                                                                                 ##STR161##         100                                   __________________________________________________________________________

                                      TABLE 19                                    __________________________________________________________________________    Pre.                                                                             reaction     Comp.                                                                             Structural          Yield                                 Ex.                                                                              reagent      No. formula             (%)                                   __________________________________________________________________________    58                                                                                ##STR162##  58                                                                                 ##STR163##         48                                    59                                                                                ##STR164##  59                                                                                 ##STR165##         92                                    60                                                                                ##STR166##  60                                                                                 ##STR167##         54                                    __________________________________________________________________________

                  TABLE 20                                                        ______________________________________                                        49    49        1.19(3H, t)1.52(3H, t)                                                                           2966                                                       1.65(3H, s)1.9˜2.3(2H, m)                                                                  1660                                                       2.39(3H, s)2.63(3H, s)                                                                           1300                                                       3.37(2H, s)3.6˜3.8(2H, m)                                                                  1120                                                       4.29(2H, q)                                                                   7.16(H, s)7.44(H, s)                                          50    50        1.59(3H, t)1.65(6H, s)                                                                           3000                                                       2.38(3H, s)2.48(3H, s)                                                                           1670                                                       2.57(3H, s)3.36(2H, s)                                                                           1305                                                       4.16(2H, q)7.20(H, s)                                                                            1140                                                       7.65(4H, dd)                                                  ______________________________________                                    

                  TABLE 21                                                        ______________________________________                                                       N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                   Pre.  Comp.    Solvent: deutero                                               Ex.   No.      chloroform         IR (cm.sup.-1)                              ______________________________________                                        51    51       1.18(3H, t)1.36(3H, d)                                                                           2930, 2970                                                 1.52(3H, t)1.9˜3.9(7H, m)                                                                  1650                                                       2.29(3H, s)2.75(3H, s)                                                                           1375, 1295                                                 3.6˜3.9(2H, m)4.22(2H, q)                                                                  1165, 1120                                                 7.11(H, s)7.44(H, s)                                           52    52       1.34(3H, d)1.50(3H, t)                                                                           2960                                                       2.1˜3.9(5H, m)2.26(3H, s)                                                                  1670                                                       2.47(3H, s)2.72(3H, s)                                                                           1385, 1310                                                 4.18(2H, q)6.96(H, s)                                                                            1130                                                       7.37(H, s)7.67(4H, dd)                                         53    53       1.18(3H, t)        3000                                                       1.44˜1.6(6H, m)                                                                            1670                                                       1.9˜2.24(2H, m)2.29(3H, s)                                                                 1400, 1310                                                 2.63(3H, s)3.2˜3.8(5H, m)                                                                  1185, 1135                                                 4.22(2H, q)                                                                   7.20(H, s)7.45(H, s)                                           54    54       1.41˜1.63(6H, m)                                                                           2990                                                       2.28(3H, s)2.47(3H, s)                                                                           1660                                                       2.57(3H, s)3.2˜3.8(3H, m)                                                                  1370, 1300                                                 4.15(2H, q)7.06(H, s)                                                                            1275, 1200                                                 7.37(H, s)7.67(4H, dd)                                                                           1120                                        ______________________________________                                    

                  TABLE 22                                                        ______________________________________                                                      N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                    Pre. Comp.    Solvent: deutero                                                Ex.  No.      chloroform         IR (cm.sup.-1)                               ______________________________________                                        55   55       1.44˜1.73(6H, m)                                                                           3000                                                       2.29(3H, s)2.63(3H, s)                                                                           1675                                                       3.2˜3.89(5H, m)4.23(2H, q)                                                                 1390, 1310                                                 7.20(H, s)7.45(H, s)                                                                             1185, 1140                                   56   56       1.28˜1.52(12H, m)                                                                          2990                                                       2.27(3H, s)2.61(3H, s)                                                                           1790                                                       2.65˜2.96(H, m)                                                                            1660, 1300                                                 3.18˜3.78(3H, m)                                                        4.02(2H, q)                                                                   7.17(H, s)7.54(H, s)                                            57   57       1.43(3H, t)1.47(3H, d)                                                                           2950                                                       2.26(3H, s)2.61(3H, s)                                                                           1780, 1660                                                 1.2˜2.5(11H, m)                                                                            1300                                                       3.2˜3.8(3H, m)                                                          4.00(2H, q)                                                                   7.16(H, s)7.58(H, s)                                            58   58       1.18(3H, t)1.52(3H, t)                                                                           not measured                                               2.25(3H, s)2.0˜2.65(4H, m)                                              2.8˜3.05(2H, m)                                                         3.3˜3.8(4H, m)4.22(2H, q)                                               7.40(H, d)7.44(H, s)                                                          7.90(H, d)                                                      ______________________________________                                    

                  TABLE 23                                                        ______________________________________                                                      N.M.R.                                                                        Internal standard: tetra-                                                     methylsilane                                                    Pre. Comp.    Solvent: deutero                                                Ex.  No.      chloroform         IR (cm.sup.-1)                               ______________________________________                                        59   59       1.50(3H, t)        not measured                                               2.20(3H, s)2.45(3H, s)                                                        2.3˜2.7(2H, m)                                                          2.85˜3.0(2H, m)                                                         3.3˜3.5(2H, m)4.15(2H, q)                                               7.2˜7.55(4H, m)7.85(2H, d)                                60   60       1.43(3H, t)2.21(3H, s)                                                                           not measured                                               1.16˜2.1(10H, m)                                                        2.33˜2.69(3H, m)                                                        2.84˜2.98(2H, m)                                                        3.28˜3.42(2H, m)4.00(2H, q)                                             7.36(H, d)7.55(H, s)                                                          7.89(H, d)                                                      ______________________________________                                    

Examples of the herbicide which achieves the second object of thepresent invention will be described hereinafter.

Herbicide Examples

(1) Preparation of Herbicide

97 Parts by weight of talc (trade name: Zeaklite) as a carrier, 1.5parts by weight of alkylarylsulfonic acid (trade name: Neoplex, suppliedby Kao-Atlas K.K.) as a surfactant and 1.5 parts by weight of a nonionicand anionic surfactant (trade name: Sorpol 800A, supplied by TohoChemical Co., Ltd. ) were uniformly pulverized and mixed to prepare acarrier for a wettable powder.

90 Parts by weight of the above carrier and 10 parts by weight of eachof Compounds obtained in the above Preparation Examples were uniformlypulverized and mixed to obtain herbicides. Further, for HerbicideComparative Examples, comparative herbicides were prepared by uniformlypulverizing and mixing 90 parts by weight of the above carrier and 10parts by weight of each of the following Compounds x, y, A, B and C.##STR168## (2) Biological test (Foliar treatment test, HerbicideExamples 1 and 2 and Herbicide Comparative Examples 1 and 2)

Seeds of weeds such as large crabgrass, barnyard grass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 1/5,000-are Wagner pots filled with upland soil, andcovered with upland soil. The seeds were grown in a greenhouse, and atthe stage of 1˜2 leaves of these plants, a predetermined amount of theherbicide prepared in the above (1) was suspended in water and uniformlysprayed onto leaf and stalk portions at a rate of 200 liter/10 are.Thereafter, the plants were grown in the greenhouse, and on 20th dayafter the treatment, the herbicide was evaluated for herbicidalefficacy. Table 124 shows the results.

The herbicidal efficacy and phytotoxcity to crops were shown on thebasis of the following ratings.

The ratio of remaining plant weight to non-treated was determined on thebasis of the ratio of remaining plant weight to non-treated=(remainingplant weight in treated plot/remaining plant weight in non-treatedplot)×100. This is also applicable to biological tests hereinafter.

    ______________________________________                                                       Ratio of remaining plant                                       (Ratings)      weight to non-treated (%)                                      ______________________________________                                        Herbicidal efficacy                                                           0               81-100                                                        1              61-80                                                          2              41-60                                                          3              21-40                                                          4               1-20                                                          5               0                                                             Phytotoxicity                                                                 to crops                                                                      -              100                                                            ±           95-99                                                          +              90-94                                                          ++             80-89                                                          +++             0-79                                                          ______________________________________                                    

                                      TABLE 24                                    __________________________________________________________________________                        Herbicidal Efficacy                                               Comp'd                                                                              Dosage                                                                              large                                                                              barnyard                                                                           green           slender                                                                            Phytotoxicity              No.     used  (g.sup.a.i. /are)                                                                   crabgrass                                                                          grass                                                                              foxtail                                                                           cocklebur                                                                           velvetleaf                                                                          amaranth                                                                           corn                                                                             wheat                                                                              barley             __________________________________________________________________________    Herbicide                                                                             1     10    5    5    5   5     5     5    -- --   --                 Example 1                                                                     Herbicide                                                                             "     3     5    5    5   5     5     5    -- --   --                 Example 1                                                                     Herbicide                                                                             2     10    5    5    5   5     5     5    -- --   --                 Example 2                                                                     Herbicide                                                                             "     3     5    4    3   5     4     3    -- --   --                 Example 2                                                                     Herbicide                                                                             x     10    0    0    0   0     0     1    -- --   --                 Comp. Exam. 1                                                                 Herbicide                                                                             y     3     0    0    0   3     3     2    -- --   --                 Comp. Exam. 2                                                                 __________________________________________________________________________

(3) Biological test (Upland soil treatment test, Herbicide Examples 3and 4 and Herbicide Comparative Examples 3 and 4)

Seeds of weeds such as large crabgrass, barnyardgrass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 1/5,000-are Wagner pots filled with upland soil, andcovered with upland soil. Then, a predetermined amount of the herbicideprepared in the above (1) was suspended in water and uniformly sprayedonto the soil surface. Thereafter, the plants were grown in thegreenhouse, and on 20th day after the treatment, the herbicide wasevaluated for herbicidal efficacy. Table 25 shows the results.

The herbicidal efficacy and the phytotoxicity to crops are shown on thebasis of the ratings described in (2) Foliar treatment test.

    __________________________________________________________________________                        Herbicidal Efficacy                                               Comp'd                                                                              Dosage                                                                              large                                                                              barnyard                                                                           green           slender                                                                            Phytotoxicity              No.     used  (g.sup.a.i. /are)                                                                   crabgrass                                                                          grass                                                                              foxtail                                                                           cocklebur                                                                           velvetleaf                                                                          amaranth                                                                           corn                                                                             wheat                                                                              barley             __________________________________________________________________________    Herbicide                                                                             1     10    5    5    5   5     5     5    -- --   --                 Example 3                                                                     Herbicide                                                                             "     3     5    5    5   5     5     5    -- --   --                 Example 3                                                                     Herbicide                                                                             2     10    5    5    5   5     5     5    -- --   --                 Example 4                                                                     Herbicide                                                                             "     3     5    5    5   5     5     5    -- --   --                 Example 4                                                                     Herbicide                                                                             x     10    0    0    0   0     0     0    -- --   --                 Comp. Exam. 3                                                                 Herbicide                                                                             y     3     3    2    2   0     0     0    -- --   --                 Comp. Exam. 4                                                                 __________________________________________________________________________

(4) Biological test (Submergence soil treatment test, Herbicide Examples5˜9 and Comparative Examples 5˜8 and Reference Examples 1 and 2)

1/15,500-are porcelain pots were filled with paddy field soil, and seedsof barnyard grass and umbrella plant were sown in a surface layer of thesoil, and paddy rice at the 2-leaf stage was transplanted. Then, theweeds were treated by uniformly spraying a diluted solution of apredetermined amount of the herbicide prepared in the above (1) onto thewater surface at the time of germination of the weeds, and then the potswere allowed to stand in a greenhouse while water was properly sprayed.Twenty days after the treatment with the herbicide solution, theherbicidal efficacy and phytotoxicity to paddy rice were inspected, andTable 26 shows the results. The dosage of each herbicide is shown as anamount of the active ingredient per 10 ares. Further, air-dried weightswere measured, and the herbicidal efficacy and the phytotoxicity to thepaddy rice were shown as follows.

    ______________________________________                                                       Ratio of remaining plant                                       (Ratings)      weight to non-treated (%)                                      ______________________________________                                        Herbicidal efficacy                                                           0               81-100                                                        1              61-80                                                          2              41-60                                                          3              21-40                                                          4               1-20                                                          5               0                                                             Phytotoxicity                                                                 to paddy rice                                                                 0              100                                                            1              95-99                                                          2              90-94                                                          3              80-89                                                          4               0-79                                                          ______________________________________                                    

                  TABLE 26                                                        ______________________________________                                                                         Phyto-                                                                        toxicity                                                  Dosage                                                                              Herbicidal Efficacy                                                                         to                                                    Comp'd    (g.sup.a.i. /                                                                         barnyard                                                                             umbrella                                                                             paddy                                No.      used      10 are) grass  plant  rice                                 ______________________________________                                        Herbicide                                                                              10        1       5      5      0                                    Example 5                                                                     Herbicide                                                                              11        1       5      5      0                                    Example 6                                                                     Herbicide                                                                              14        1       5      3      0                                    Example 7                                                                     Herbicide                                                                              16        3       5      5      0                                    Example 8                                                                     Herbicide                                                                              "         1       5      2      0                                    Example 9                                                                     Comparative                                                                            Comp'd A  3       4      4      4                                    Example 5                                                                     Comparative                                                                            "         1       1      0      0                                    Example 6                                                                     Comparative                                                                            Comp'd B  3       5      5      4                                    Example 7                                                                     Comparative                                                                            "         1       2      3      0                                    Example 8                                                                     Reference                                                                              Comp'd C  10      4      5      5                                    Exam. 1                                                                       Reference                                                                              "         3       0      3      2                                    Exam. 2                                                                       ______________________________________                                         .sup.a.i. = active ingredient                                            

(5) Biological test (Upland soil treatment test, Herbicide Examples10˜26 and Comparative Example 9)

Seeds of weeds such as large crabgrass, barnyard grass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 5,000-are Wagner pots filled with upland soil, andcovered with upland soil. Then, a predetermined amount of the herbicideprepared in the above (1) was suspended in water and uniformly sprayedonto the soil surface. Thereafter, the plants were grown in thegreenhouse, and on 20th day after the treatment, the herbicide wasevaluated for herbicidal efficacy. Table 27 shows the results.

The dosage of each herbicide is indicated as an amount of the activeingredient per hectare. Further, air-dried weight were measured, andherbicidal efficacy and the phytotoxicity to corn are shown on the basisof the ratings described below.

    ______________________________________                                                       Ratio of remaining plant                                       (Ratings)      weight to non-treated (%)                                      ______________________________________                                        Herbicidal efficacy                                                           0               81-100                                                        1              61-80                                                          2              41-60                                                          3              21-40                                                          4               1-20                                                          5               0                                                             Phytotoxicity                                                                 to corn                                                                       0              100                                                            1              95-99                                                          2              90-94                                                          3              80-89                                                          4               0-79                                                          ______________________________________                                    

                                      TABLE 27                                    __________________________________________________________________________                         Herbicidal efficacy                                             Comp'd Dosage large barnyard                                                                           green             slender                                                                            Phytotoxicity          No.    used   (g.sup.a.i. /hectare)                                                                crabgrass                                                                           grass                                                                              foxtail                                                                            cocklebur                                                                           velvetleaf                                                                           amaranth                                                                           to                     __________________________________________________________________________                                                           corn                   Herbicide                                                                             1     100    5     5    5    5     5      5    0                      Example 10                                                                    Herbicide                                                                             2     100    5     5    5    5     5      5    0                      Example 11                                                                    Herbicide                                                                             7     100    5     5    4    5     5      5    0                      Example 12                                                                    Herbicide                                                                             8     100    5     4    4    5     5      --   0                      Example 13                                                                    Herbicide                                                                             9     100    5     5    5    5     5      5    0                      Example 14                                                                    Herbicide                                                                            10     100    5     5    2    3     5      5    0                      Example 15                                                                    Herbicide                                                                            11     100    5     3    2    3     5      1    0                      Example 16                                                                    Herbicide                                                                            12     100    5     5    1    --    5      5    0                      Example 17                                                                    Herbicide                                                                            13     100    5     3    2    5     5      2    0                      Example 18                                                                    Herbicide                                                                            14     100    5     5    2    5     5      5    0                      Example 19                                                                    Herbicide                                                                            16     100    5     5    5    5     5      5    0                      Example 20                                                                    Herbicide                                                                            18     100    5     5    4    5     5      5    0                      Example 21                                                                    Herbicide                                                                            19     100    5     5    2    5     5      5    0                      Example 22                                                                    Herbicide                                                                            20     100    5     3    2    5     5      --   0                      Example 23                                                                    Herbicide                                                                            21     100    5     5    4    5     5      5    0                      Example 24                                                                    Herbicide                                                                            24     100    5     5    2    5     5      5    0                      Example 25                                                                    Herbicide                                                                            25     100    5     2    2    5     5      5    0                      Example 26                                                                    Comparative                                                                          Comp'd A                                                                             100    1     2    4    1     5      3    0                      Example 9                                                                     __________________________________________________________________________     .sup.a.i. = active ingredient                                            

(6) Biological test (Upland soil treatment test, Herbicide Examples27˜42 and Comparative Example 10).

Seeds of weeds such as large crabgrass, barnyard grass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 1/5,000-are Wagner pots filled with upland soil, andcovered with upland soil. Then, a predetermined amount of the herbicideprepared in the above (1) was suspended in water and uniformly sprayedonto the soil surface. Thereafter, the plants were grown in thegreenhouse, and on 20th day after the treatment, the herbicide wasevaluated for herbicidal efficacy. Table 28 shows the results.

The dosage of each herbicide is indicated as an amount of the activeingredient per hectare. Further, air-dried weights were measured and theherbicidal efficacy and the phytotoxicity to corn are shown on the basisof the ratings described below.

    ______________________________________                                                       Ratio of remaining plant                                       (Ratings)      weight to non-treated (%)                                      ______________________________________                                        Herbicidal efficacy                                                           0               81-100                                                        1              61-80                                                          2              41-60                                                          3              21-40                                                          4               1-20                                                          5               0                                                             Phytotoxicity                                                                 to corn                                                                       0              100                                                            1              95-99                                                          2              90-94                                                          3              80-89                                                          4               0-79                                                          ______________________________________                                    

                                      TABLE 28                                    __________________________________________________________________________    Herbicide                                                                            Comp'd Dosage Herbicidal efficacy     Phytotoxicity                    Exam. No.                                                                            used   (g/hectare)                                                                          (A) (B) (C) (D) (E) (F) to corn                          __________________________________________________________________________    27     29     100    5   4   4   5   5   5   0                                28     30     100    5   4   3   1   5   5   0                                29     31     100    5   4   3   1   4   5   0                                30     44     100    5   5   5   5   5   5   0                                31     46     100    5   5   5   2   1   1   0                                32     48     100    5   5   1   1   5   5   0                                33     49     100    5   5   5   5   5   5   0                                34     50     100    4   5   5   5   5   4   0                                35     51     100    5   5   5   5   5   5   0                                36     52     100    5   5   5   5   5   5   0                                37     53     100    5   5   4   2   5   1   0                                38     54     100    5   5   4   1   5   1   0                                39     56     100    5   5   4   5   5   5   0                                40     57     100    5   5   4   5   5   5   0                                41     59     100    5   5   4   0   5   5   0                                42     60     100    5   3   3   1   5   5   0                                Comp.  Conp'd A                                                                             100    1   2   4   1   5   3   0                                Exam. 10                                                                      __________________________________________________________________________     (A): large crabgrass                                                          (B): barnyard grass                                                           (C): green foxtail                                                            (D): cocklebur                                                                (E): velvetleaf                                                               (F): slender amaranth                                                    

(7) Biological test (Foliar treatment test, Herbicide Examples 43-47 andComparative Examples 11 and 12)

Seeds of weeds such as large crabgrass, barnyardgrass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 1/5,000-are Wagner pots filled with upland soil, andcovered with upland soil. The seeds were grown in a greenhouse, and atthe stage of 1˜2 leaves of these plants, a predetermined amount of theherbicide prepared in the above (1) was suspended in water and uniformlysprayed onto leaf and stalk portions at a rate of 200 liter/10 ares.Thereafter, the plants were grown in the greenhouse, and on 20th dayafter the spraying treatment, the herbicide was evaluated for herbicidalefficacy. Table 29 shows the results.

The herbicidal efficacy and phytotoxcity to crops were shown on thebasis of the following ratings.

The ratio of remaining plant weight to non-treated was determined on thebasis of the ratio of remaining plant weight to non-treated=(remainingplant weight in treated plot/remaining plant weight in non-treatedplot)×100. This is also applicable to biological tests hereinafter.

    ______________________________________                                                       Ratio of remaining plant                                       (Ratings)      weight to non-treated (%)                                      ______________________________________                                        Herbicidal efficacy                                                           0               81-100                                                        1              61-80                                                          2              41-60                                                          3              21-40                                                          4               1-20                                                          5               0                                                             Phytotoxicity                                                                 to corn                                                                       -              100                                                            ±           95-99                                                          +              90-94                                                          ++             80-89                                                          +++             0-79                                                          ______________________________________                                    

                                      TABLE 29                                    __________________________________________________________________________                        Herbicidal Efficacy                                       Herbicide                                                                            Comp'd                                                                             Dosage  large                                                                              barnyard                                                                           green           slender                                                                            Phytotoxicity              Exam. No.                                                                            No.  (g.sup.a.i. /hectare)                                                                 crabgrass                                                                          grass                                                                              foxtail                                                                           cocklebur                                                                           velvetleaf                                                                          amaranth                                                                           corn                                                                             wheat                                                                              barley             __________________________________________________________________________    43     43   300     5    5    5   5     5     5    -- --   --                 44     49   300     5    5    5   5     5     5    -- --   --                 45     50   300     5    5    5   5     5     5    -- --   --                 46     47-1 300     0    0    0   5     4     0    -- --   --                 47     47-2 300     5    2    5   5     5     5    -- --   --                 Comp.  x    1000    0    0    0   0     0     0    -- --   --                 Exam. 11                                                                      Comp.  y    300     0    0    0   3     3     2    -- --   --                 Exam. 12                                                                      __________________________________________________________________________     .sup.a.i. = active ingredient                                            

(8) Biological test (Upland soil treatment test, Herbicide Examples48-52 and Herbicide Comparative Examples 13 and 14)

Seeds of weeds such as large crabgrass, barnyard grass, green foxtail,cocklebur, velvetleaf and slender amaranth and seeds of corn, wheat andbarley were sown in 1/5,000-are Wagner pots filled with upland soil, andcovered with upland soil. Then, a predetermined amount of the herbicideprepared in the above (1) was suspended in water and uniformly sprayedonto the soil surface. Thereafter, the plants were grown in thegreenhouse, and on 20th day after the spraying treatment, the herbicidewas evaluated for herbicidal efficacy. Table 30 shows the results.

The herbicidal efficacy and the phytotoxicity to crops are shown on thebasis of the ratings described in (2) Foliar treatment test.

                                      TABLE 30                                    __________________________________________________________________________                        Herbicidal Efficacy                                       Herbicide                                                                            Comp'd                                                                             Dosage  large                                                                              barnyard                                                                           green           slender                                                                            Phytotoxicity              Exam. No.                                                                            No.  (g.sup.a.i. /hectare)                                                                 crabgrass                                                                          grass                                                                              foxtail                                                                           cocklebur                                                                           velvetleaf                                                                          amaranth                                                                           corn                                                                             wheat                                                                              barley             __________________________________________________________________________    48     43   300     5    5    5   5     5     5    -- --   --                 49     49   300     5    5    5   5     5     5    -- --   --                 50     50   300     5    5    5   5     5     5    -- --   --                 51     47-1 300     0    0    0   0     0     5    -- --   --                 52     47-2 300     1    5    4   0     5     5    -- --   --                 Comp.  x    1000    0    0    0   0     0     1    -- --   --                 Exam. 13                                                                      Comp.  y    300     3    3    2   0     0     0    -- --   --                 Exam. 14                                                                      __________________________________________________________________________     .sup.a.i. = active ingredient                                            

As explained in detail above, there are provided novel pyrazolederivatives which can selectively control gramineous weeds andbroad-leaved weeds together by any one of Foliar treatment and soiltreatment at a low dosage without causing phytotoxicity on useful cropssuch as rice, corn, wheat, barley, and the like, herbicides containingthe above novel pyrazole derivatives as active ingredients, andintermediate compounds suitable for the production of the above novelpyrazole derivatives.

What is claimed is:
 1. A pyrazole derivative of the general formula (I),##STR169## wherein: R¹ is one member selected from the group consistingof hydrogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group and aC₂ ˜C₄ alkoxyalkyl group;R² is one member selected from the groupconsisting of a alkyl group, a C₂ ˜C₄ alkenyl group and a C₂ ˜C₄haloalkenyl group; X¹ is one member selected from hydrogen atom, halogenatom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group, a C₂ ˜C₄alkoxyalkyl group, a C₁ ˜C₄ alkoxy group and a C₁ ˜C₄ haloalkoxy group;each of X² and X³ is independently one member selected from the groupconsisting of hydrogen atom, a C₁ ˜C₄ alkyl group and a C₁ ˜C₄ haloalkylgroup; X⁴ is one member selected from the group consisting of hydrogenatom, halogen atom, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄ haloalkyl group andC₁ ˜C₄ alkoxy group; each of X⁵, X⁶, X⁷ and X⁸ is independently hydrogenatom or a C₁ ˜C₄ alkyl group; further, a combination of X² and X⁵ or acombination of X⁵ and X⁷ may be an unsaturated bond; n is an integer of0, 1 or 2; p is an integer of 0 or 1; and Q is hydrogen or any one ofthe following groups (a) to (h), ##STR170## in which R³ is one memberselected from the group consisting of a C₁ ˜C₈ alkyl group, a C₃ -C₈cycloalky group and a group of the general formula (V), ##STR171## inwhich Y is halogen atom, nitro group, a C₁ ˜C₄ alkyl group, a C₁ ˜C₄alkoxy group or a C₁ ˜C₄ haloalkyl group, and m is an integer of 0, 1 or2, R⁴ is one member selected from the group consisting of a C₁ ˜C₈ alkylgroup, a C₃ -C₈, cycloalkyl group, pyridyl group and a group of thegeneral formula (V), R⁵ is hydrogen or a C₁ ˜C₄ alkyl group, R⁶ is onemember selected from the group consisting of hydrogen, a C₁ ˜C₄ alkylgroup and a group of the general formula (V), and each of R⁷ and R⁸ isindependently hydrogen or a C₁ ˜C₄ alkyl group, and a salt thereof. 2.The pyrazole derivative or the salt thereof according to claim 1,wherein R¹ is hydrogen atom or a C₁ ˜C₄ alkyl group.
 3. The pyrazolederivative or the salt thereof according to claim 2, wherein the C₁ ˜C₄alkyl group is methyl.
 4. The pyrazole derivative or the salt thereofaccording to claim 1, wherein R² is a C₁ ˜C₄ alkyl group.
 5. Thepyrazole derivative or the salt thereof according to claim 4, whereinthe C₁ ˜C₄ alkyl group is methyl or ethyl.
 6. The pyrazole derivative orthe salt thereof according to claim 1, wherein X¹ is one member selectedfrom the group consisting of hydrogen atom, a C₁ ˜C₄ alkyl group andhalogen atom.
 7. The pyrazole derivative or the salt thereof accordingto claim 6, wherein the C₁ ˜C₄ alkyl group is methyl.
 8. The pyrazolederivative or the salt thereof according to claim 7, wherein the halogenatom is chlorine.
 9. The pyrazole derivative or the salt thereofaccording to claim 1, wherein each of X² and X³ is independently a C₁˜C₄ alkyl group.
 10. The pyrazole derivative or the salt thereofaccording to claim 9, wherein each of X² and X³ is methyl.
 11. Thepyrazole derivative or the salt thereof according to claim 1, whereineach of X² and X³ is hydrogen.
 12. The pyrazole derivative or the saltthereof according to claim 1, wherein one of X² and X³ is hydrogen andthe other thereof is methyl.
 13. The pyrazole derivative or the saltthereof according to claim 1, wherein X⁴ is hydrogen, or a C₁ ˜C₄ alkylgroup or halogen atom substituted on the 8-position of the thiochromanring.
 14. The pyrazole derivative or the salt thereof according to claim13, wherein the C₁ ˜C₄ alkyl group is methyl.
 15. The pyrazolederivative or the salt thereof according to claim 13, wherein thehalogen atom is chlorine.
 16. The pyrazole derivative or the saltthereof according to claim 1, wherein each of X⁵, X⁶, X⁷ and X⁸ ishydrogen atom.
 17. The pyrazole derivative or the salt thereof accordingto claim 1, wherein p is
 1. 18. The pyrazole derivative or the saltthereof according to claim 1, wherein p is
 0. 19. The pyrazolederivative or the salt thereof according to claim 1, wherein Q ishydrogen.
 20. The pyrazole derivative or the salt thereof according toclaim 1, wherein Q is a group of --SO₂ --R³.
 21. The pyrazole derivativeor the salt thereof according to claim 20, wherein the group of --SO₂--R³ is one member selected from the group consisting of ##STR172## 22.The pyrazole derivative or the salt thereof according to claim 1,wherein Q is a group of ##STR173##
 23. The pyrazole derivative or thesalt thereof according to claim 22, wherein the group of ##STR174## isone member selected from the group consisting of ##STR175##
 24. Thepyrazole derivative or the salt thereof according to claim 22, whereinthe group of ##STR176##
 25. The pyrazole derivative or the salt thereofaccording to claim 1, wherein Q is ##STR177##
 26. The pyrazolederivative or the salt thereof according to claim 25, wherein the groupof ##STR178## is one member selected from the group consisting of##STR179##
 27. The pyrazole derivative or the salt thereof according toclaim 1, wherein Q is ##STR180##
 28. The pyrazole derivative or the saltthereof according to claim 27, wherein the group of ##STR181##
 29. Thepyrazole derivative or the salt thereof according to claim 1, wherein Qis ##STR182##
 30. The pyrazole derivative or the salt thereof accordingto claim 28, wherein the group of ##STR183##
 31. The pyrazole derivativeor the salt thereof according to claim 1, wherein Q is ##STR184## 32.The pyrazole derivative or the salt thereof according to claim 31,wherein the group of ##STR185## is one member selected from the groupconsisting of ##STR186##
 33. A herbicidal composition comprising, (i) asan active ingredient, the pyrazole derivative of the general formula (I)recited in claim 1 and/or its salt, and (ii) a carrier.